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Part 2 book “General and molecular pharmacology” has contents: Control of drug plasma concentration, drug–receptor interactions- quantitative and qualitative aspects, receptors and modulation of their response, adaptation to drug response and drug dependence, pharmacological modulation of posttranslational modifications, calcium homeostasis within the cells,… and other contents.
SECTION PHARMACOLOGICAL CONTROL OF MEMBRANE TRANSPORT 27 ION CHANNELS Maurizio Taglialatela and Enzo Wanke By reading this chapter, you will: • Become familiar with the main principles governing function, structural organization, and classification of ion channels • Know the role(s) played by the main classes of ion channels in different organs, tissues, and cells • Know the clinical applications of drugs interfering with the function of each ion channel class • Learn how functional changes resulting from drug‐ induced modulation of ion channels can be exploited for therapeutic purposes ION CHANNELS AND TRANSPORTERS Eukaryotic cells use about 30% of their energy to maintain the transmembrane gradients of protons (H+), sodium (Na+), potassium (K+), chloride (Cl−), and calcium (Ca2+), an indi cation of their paramount importance for cell survival and replication On purely thermodynamic grounds, transmembrane trans port mechanisms can be classified into active and passive Passive processes transport ions from the side of the mem brane with high electrochemical potential to the side with low electrochemical potential Two types of proteins are responsible for passive ion transport: facilitated transporters and ion channels (Fig. 27.1), with very different transport mechanisms Substrate binding to the transporter on one side of the membrane induces a conformational change, resulting in exposure of the substrate on the opposite side of the membrane The substrate concentration gradient provides the energy required for the process; as the substrate movement is coupled to a conformational change of the transporter, the transfer rate is rather low By contrast, ion channels contain aqueous pores through which permeating ions can flow at very high rates (>106/s, close to the diffusion rate in water), thus generating significant currents that may rapidly change the resting membrane potential (VREST) of a cell Both these passive processes dissipate the energy gra dient established by active transporters, which pump ions across the membrane against their concentration gradients This process requires an energy input generally provided by ATP hydrolysis (primary active transporters) Otherwise, movement of a solute against the electrochemical gradient can be coupled to the movement of another solute down its electrochemical gradient, either in the same direction (cotransport or symport) or in the opposite (countertransport or antiporter) Enormous progresses in the structural and functional characterization of membrane transport over the last 10–15 years have made the separation line between ion chan nels and transporters progressively thinner Recent studies have shown that some toxins can convert a transporter into an ion channel and that transporters and channels can coexist within the same structural family For instance, in the “ATP‐ binding cassette” (ABC) family of transporters, the cystic fibrosis transmembrane regulator (CFTR, so called as it is mutated in cystic fibrosis) is the only channel member; moreover, the Cl‐ channel family includes both ion channels (CLC‐0, CLC‐1, and CLC‐2) and transporters (CLC‐4 and CLC‐5) Finally, within the same family, CLC‐0, CLC‐1, and CLC‐2 are ion channels in vertebrates, whereas their bacterial counterparts behave like transporters General and Molecular Pharmacology: Principles of Drug Action, First Edition Edited by Francesco Clementi and Guido Fumagalli © 2015 John Wiley & Sons, Inc Published 2015 by John Wiley & Sons, Inc 312 ION CHANNELS Carrier Channel Closed Extracellular SL Open SL Intracellular Figure 27.1 Ion channels and transporters The cartoon depicts the conceptual difference between ion channels and transporters For ion channels (left), ions diffuse through the open pore, which is thought to be controlled by one gate For transporters (right), the transport pathway is guarded by at least two gates whose opening is coordinated so that no high conductance open pore is allowed “SL” represents the transported substrate that binds to the binding site in the conduction pathway (Modified from Ref [1]) CHARACTERIZATION AND FUNCTION OF ION CHANNELS In excitable cells like muscle cells, endocrine cells, and neu rons, ion channels are responsible for generation and regula tion of electrical signals required for coordinated contraction of skeletal muscle, hormonal secretion, and neurotransmitter release; furthermore, in all cells, they control cell volume and motility With modern electrophysiological and molecular biology techniques, several genes encoding ion channels have been identified, and the specific functional properties of their pro tein products have been characterized Besides suggesting the molecular basis for the action of specific drug classes, these studies have also allowed to discover that genetically determined ion channel defects can be responsible for sev eral human diseases (the so‐called human channelopathies; see Table 27.1) To understand the mechanism of action of drugs acting on ion channels, it is essential to recapitulate some fundamental concepts on the functional and structural properties of ion channel proteins Channel Classification According to Permeating Ions and Gating Mechanisms Ion channels can be classified according to purely functional criteria Two main properties characterize the activity of a specific ion channel: the mechanism triggering its gating and the ion species flowing through it In voltage‐gated ion channels (VGICs), representing the third largest class of proteins involved in signal transduction, the gating trigger is represented by changes in transmem brane voltage; even few millivolts can drastically alter the opening probability of VGICs Other gating mechanisms are represented by changes in the chemical composition of the intra‐ or extracellular environment (ligand‐gated ion chan nels (LGICs); see Chapter 16), in the applied mechanical force (mechanosensitive channels), or in the environmental temperature (thermosensitive channels) Obviously, this schematic classification is an oversimplification, as several mechanisms often contribute to regulate ion channel activity in distinct pathophysiological states; for example, Ca2+‐ dependent K+ channels are also sensitive to changes in trans membrane voltage, some VGICs are also sensitive to changes in osmotic pressure, and some LGICs are also influenced by changes in transmembrane voltage and environmental temperature Permeation characteristics allow classifying ion channels based on their ion selectivity (with Na+, K+, Ca2+, and Cl− channels showing the greatest selectivity) Further classi fication criteria, such as cell‐ or tissue‐specific expression or peculiar sensitivity to drugs and toxins, can further contribute to characterize ion channel classes Having introduced permeation and gating as the two main criteria for ion channel classification, now we will briefly describe these two functional properties Permeation and Concentration Gradients Ion channels having the same selectivity are often discrimi nated based on their conductance (γ), which is the ratio between current carried (i) and electromotive force (V), the latter defined as the sum of the electrical and chemical gradient acting on the ion In fact, each ion is subjected to both electrical forces (the membrane potential VM is the difference between the cytoplasmic and the extracellular charges) and diffusional forces (produced by the ion concentration gradient between the intracellular and extra cellular space) The equilibrium between these two forces is the Nernst potential (or reversal potential) The Nernst potential depends on the logarithm of the ion concentration ratio between the extracellular and intracellular environ ment, according to the equation E Nernst 60 log I out I in where [I+]out and [I+]in are the extracellular and intracellular concentrations, respectively, of the ion I In most animal cells, the Nernst potentials for the various ions (ENa, EK, ECl, ECa, etc.) are +70 mV for ENa, −95 mV for EK, −30/−60 mV for ECl, and +150 mV for ECa Thus, opening of a single ion channel species (i.e., that for K+) will generate a current 313 HYPERK‐ PP PMC PAM CMS IEM PEPD CIP TM Hyperkalemic periodic paralysis Paramyotonia congenita Potassium‐aggravated myotonia Congenital myasthenic syndrome Hereditary erythermalgia Paroxysmal extreme pain disorder Congenital pain insensitivity Thomsen myotonia (dominant) HYPOK‐ PP Hypokalemic periodic paralysis Kidney polycystic disease Spinocerebellar ataxia Familial hemiplegic migraine Familial sinus bradycardia Episodic ataxia Brugada syndrome Progressive cardiac conduction disease Sick sinus syndrome Short QT syndrome SCN4A SCN4A SCN4A SCN9A SCN9A SCN9A CLCN1 SCN4A SCN4A 17 17 17 17 17 2 CACNA1C SCNA4B SCN5A SCN5A SCN5A KCNQ1 KCNH2 KCNJ2 CACNA1C HCN4 KCNA1 CACNA1A CACNA1A CACNA1A SCN1A PDK1 PDK2/TRPP2 CaCNA1S Andersen–Tawil syndrome KCNH2 SCN5A KCNE1 KCNE2 KCNJ2 KCNQ1 KCNQ1 KCNQ2 KCNQ3 KCNQ4 Channel 21 11 3 11 17 21 15 12 19 19 19 16 21 21 17 LQTS‐2 LQTS‐3 LQTS‐5 LQTS‐6 LQTS‐7 LQTS‐8 LQT‐10 BrS PCCD SSS SQTS SQTS SQTS SQTS/BrS FSB EA‐1 EA‐2/EA‐5 SCA6 FHM1 FHM3 PKD 11 11 LQTS‐1 LQTS‐1 Autosomal congenital deafness type Long QT syndrome Romano–Ward (dominant) Jervell/Lange‐Nielsen (recessive) Timothy syndrome 20 BFNC1 BFNC2 DFNA‐2 Benign familial neonatal convulsions Chromosome Acronym Disease name Table 27.1 Main hereditary diseases caused by ion channel mutations (channelopathies) (Continued ) Skeletal muscle hyperexcitability High [K+]o‐aggravated myotonia Myasthenia Pain hypersensitivity (gain‐of‐function mutations) Pain hypersensitivity (gain‐of‐function mutations) Analgesia (loss‐of‐function mutations) Myotonia Low [K+]o‐triggered skeletal muscle paralysis High [K+]o‐triggered skeletal muscle paralysis Cardiac arrhythmias (loss‐of‐function mutations) Cardiac arrhythmias and deafness (loss‐of‐function mutations) Cardiac arrhythmias (loss‐of‐function mutations) Cardiac arrhythmias Cardiac arrhythmias Cardiac arrhythmias Cardiac arrhythmias (loss‐of‐function mutations), periodic paralysis, and dysmorphic features Cardiac arrhythmias (gain‐of‐function mutations) Cardiac arrhythmias Cardiac arrhythmias Cardiac arrhythmias with conduction disorders Cardiac arrhythmias with conduction disorders Cardiac arrhythmias (gain‐of‐function mutations) Cardiac arrhythmias (gain‐of‐function mutations) Cardiac arrhythmias (gain‐of‐function mutations) Cardiac arrhythmias (loss‐of‐function mutations) Sinus bradycardia Ataxia, migraine, neurodegeneration Ataxia Ataxia, migraine Migraine Migraine Hypertension, kidney disorders Hypertension, kidney disorders Low [K+]o‐triggered skeletal muscle paralysis Increased neuronal excitability, epilepsia Increased neuronal excitability, epilepsia Deafness Phenotype 314 SUR1 11 12 X 16 X |BD LD PHHI PNDM TNDM CMD1O DD ADO, ARO CF CSNB2 Nesidioblastosis Persistent neonatal diabetes Transient neonatal diabetes Cardiomyopathy (with ventricular arrhythmia) Dent disease Osteopetrosis Cystic fibrosis Congenital stationary night blindness type 11 11 11 KCNJ1 SCNN1A (Epithelial channel) KCNJ11 11 12 CPVT Congenital paroxysmal ventricular tachycardia Bartter disease Liddle disease CLCN5 CLCN7 CFTR CACNA1F SUR2A KCNJ11 KCNJ11 CLCN1 RYR1 CACNA1S RYR2 19 1 BM MH Channel Becker myotonia (recessive) Malignant hyperthermia Chromosome Acronym Disease name Table 27.1 (Continued ) Proximal tubulopathy with kidney failure Defect in osteoclast‐mediated bone reabsorption Altered exocrine secretion of chloride Changes in vision Infantile hyperinsulinemia (loss‐of‐function mutations) Infantile hyperinsulinemia (loss‐of‐function mutations) Neonatal diabetes (gain‐of‐function mutations); also in SUR1 Neonatal diabetes (gain‐of‐function mutations); also in SUR1 Dilative cardiomyopathy; ventricular arrhythmias Hypokalemic alkalosis Hypertension; pseudohyperaldosteronism (gain‐of‐function mutations) Myotonia Drug hypersensitivity with hyperthermia attacks Low [K+]o‐triggered skeletal muscle paralysis Cardiac arrhythmias Phenotype CHARACTERIZATION AND FUNCTION OF ION CHANNELS 315 Inactivation Inactivation Activation Closed α (VM, [Ca2+], …) γ (VM, [Ca2+], …) Open β (VM, [Ca2+], …) Inactivated δ (VM, [Ca2+], …) Recovery from inactivation Deactivation Recover from inactivation Figure 27.2 Kinetic states of ion channels For each ion channel, irrespectively of the gating mechanism, kinetic models can be elabo rated to account for the equilibrium among closed, open, and inactivated states by defining kinetic constants (α, β, γ, δ, etc.), which depend on variables such as VM, [Ca2+]i, [cAMP]i, pHi, and others [according to the Ohm’s law: i = γ × (VM−ENernst)] that will drive membrane potential VM toward the Nernst potential for the only permeating ion (K+, EK) Since in most cells the resting conductance for K+ ions is larger than that for any other ion species, VREST will be generally negative (between −40 and −90 mV) and close to EK When channels permeable to multiple ion species are open, VREST reaches a value for which the algebraic sum of all inward and outward currents carried by the open channels is zero It should be reminded that, by definition, inward currents are carried either by cat ions entering the cell or by anions flowing toward the extra cellular space, whereas outward currents are due to cations leaving the cytoplasm or by anions entering the cell Therefore, in most physiological conditions, inward currents cause membrane depolarization, whereas outward currents hyperpolarize the membrane Transmembrane Voltage Triggers Conformational Changes The membrane potential, VM, is the main regulator of the opening probability of VGICs Most VGICs are activated (opened) by membrane depolarization, though few of them are activated by membrane hyperpolarization In muscle and neuronal cells, VREST is rather negative (about −60 mV or less) Therefore, activation of ion channels selective for Na+ and Ca2+ ions (which are normally closed at VREST and become active upon membrane depolariza tion) will generate a cation flux, further amplifying plasma membrane depolarization Vice versa, activation of outward currents carried by K+ and Cl− channels represents the primary mechanism by which cells repolarize (or hyper polarize) VREST As described in Figure 27.2, in VGICs, the transition bet ween closed and open state is defined as activation; vice versa, the term deactivation refers to the reverse transition, from open to closed In some channels, in addition to the closed and open states, an inactivated state exists, generated (a) (b) Non-rectifying +1 I(nA) I V(mV) –100 (c) Inward rectifying +100 Outward rectifying I V V –1 Figure 27.3 Current–voltage (I/V) relationships in ion channels and rectification process by a process called inactivation In the inactivated state, similarly to the closed state, ions cannot flow through the channel pore; however, in contrast to closed channels, inac tivated channels cannot be reopened by depolarization, but need to return to the closed state from which the activation process can proceed This process, defined as recovery from inactivation, generally requires cell repolarization to rather negative values of membrane potential Both in the inactivation and in the recovery from inactivation processes, the channel can transit through the open state These distinct functional states (closed, open, inactivated) correspond to different conformations of the channel pro tein; this has important pharmacological consequences, as most drugs acting on ion channels interact differently with each state, thus showing state‐dependent actions (see the succeeding text) Current–Voltage Relationships and The Rectification Process As previously illustrated, the Ohm’s law allows calculating how electromotive forces influence currents carried by ion channels In ion channels, the voltage dependence of ion channel current is experimentally measured and graph ically represented by the current–voltage (I/V) relationship (Fig. 27.3) Each class of ion channel presents a “signa ture” I/V, whose shape depends on the specific permeation 316 ION CHANNELS and gating properties of the channel Panel a in Figure 27.3 shows the I/V relationship of a channel whose conductance is constant across the entire voltage range; a linear I/V indicates that the channel conductance, corresponding to the slope of the I/V relationship, is independent of voltage Vice versa, if the conductance changes as a function of the voltage examined and the I/V is not linear across the entire voltage range examined, the channel is said to show recti fication Such divergence from the Ohm’s law may take two forms: in inwardly rectifying channels, membrane conductance is larger at more negative potentials, as these channels preferentially conduct inward currents (panel b); the opposite is true in outwardly rectifying channels, which preferentially carry outward currents at depolarized poten tials (panel c) STRUCTURAL ORGANIZATION OF ION CHANNELS VGICs are integral membrane proteins with a molecular mass of about 200–250 kDa Na+ and Ca2+ channels consist of a single large polypeptide (α‐subunit) containing four homologous domains of 300–400 amino acids (domains I, II, III, and IV) (Fig. 27.4) Instead, voltage‐gated K+ chan nels result from the association of four smaller subunits, each corresponding to one of the domains of Na+ and Ca2+ channels, to form a functional tetrameric channel Sequence analysis suggests that voltage‐gated K+ channel subunits are phylogenetic ancestors of Na+ and Ca2+ channel α‐subunits (Fig. 27.4, top line), generated during evolution by gene duplication/fusion mechanisms The higher degree of ge netic heterogeneity occurring in K+ over Ca2+ and, especially, Na+ channels (Fig. 27.4, line “families”) supports this hypo thesis, as the longer the existence of a protein, the higher its genetic heterogeneity Sequence homology among domains/ subunits of K+, Na+, and Ca2+ channels is very high, whereas the intervening regions between domains are more divergent In all VGICs, each domain (or subunit) contains six segments (S1–S6) formed by mostly hydrophobic amino acids, which are likely to adopt a transmembrane topology In the tetrameric structure, segments S5 and S6 occupy a central position, whereas the other segments are placed more radially Each of these segments, as well as their join ing regions, likely play a specific role in activation, inac tivation, and selective permeability As already introduced, genetic and structural heteroge neity is largest in K+ channels; in fact, voltage‐independent K+ channels of the “inward‐rectifier” type consist of sub units with only two transmembrane domains (Fig. 27.4) Recently, genes encoding K+ channel subunits characterized by two transmembrane segments repeated in tandem (4 transmembrane segments in total) have also been identified The linker region between these two transmembrane segments is highly homologous to that between the S5 and S6 segments in classical voltage‐gated K+ channels and likely contributes to formation of the ion channel pore (see the succeeding text) On the other hand, these subunits with 2 or transmembrane segments lack the S4 segment (the “voltage sensor”; see the succeeding text), explaining why channels containing these subunits are not regulated by changes in membrane voltage Besides the main pore‐forming subunits, both voltage‐ dependent and voltage‐independent channels contain a variable number and type of accessory subunits, contrib uting to correct assembly, trafficking, and plasma mem brane localization, as well as to peculiar pathophysiological and pharmacological properties of the ion channel complex Different genes belonging to the same class or alternatively spliced variants of the same gene contribute to functional heterogeneity of ion channels expressed in different tissues or cell types The Voltage Sensor of VGICs In VGICs, changes in transmembrane voltage trigger pore opening Thus, VGICs must contain a voltage sensor that “senses” the transmembrane electric field and undergoes conformational changes in response to changes in the electric field Hodgkin and Huxley, in the 1950s, were the first to hypothesize the existence of charged particles within the ion channel region sensing the transmembrane electric field and triggering voltage‐dependent gating when displaced Hodgkin and Huxley named them “gating charges.” In squid giant axon, currents generated by translocation of these gating charges within the membrane electric field were directly recorded in the 1970s in both voltage‐gated Na+ and K+ channels (“gating currents”) In the 1980s, the primary sequences of the first VGIC genes (first, the Na+ channel from electric fishes and rat brain, then the rabbit skeletal muscle Ca2+ channel, and, finally, the Drosophila K+ channel named Shaker) were obtained Sequence inspection revealed the presence of an amino acid stretch containing 4–8 positively charged residues (lysines and arginines) every three position and spaced by mostly hydrophobic residues in the fourth transmembrane segment (S4) of each of the four homologous domains of the Na+ and Ca2+ channel α‐subunits and in each K+ channel subunit It was then suggested that these positive charges in S4 could be the gating charges of VGICs and that, following changes in transmembrane voltage, their movement could represent the first conforma tional change leading to channel opening Both in the resting and activated configurations of the voltage sensor, S4 positive charges would establish distinct electrostatic contacts with the negative charges of other amino acid residues (also highly conserved among different VGICs) in the S1, S2, and S3 segments of the same domain/subunit or of the membrane phospholipid head groups STRUCTURAL ORGANIZATION OF ION CHANNELS 317 Figure 27.4 Structure‐based classification of ion channels Superfamilies of Na+, Ca2+, and K+ channels are outlined in the first and second lines Voltage‐gated Na+ channel (VGNC) and voltage‐gated Ca2+ channel (VGCC) genes encode for proteins (α‐subunits) with four highly homologous domains, each containing transmembrane segments (6TM); instead, voltage‐gated K+ channel (VGKC) genes encode for 6TM α‐subunits analogous to one of the four domains of the VGNCs and VGCCs; VGKCs assemble as homo‐ or heterotetramers In addition, a large gene family of non‐VGKC genes encode for 2TM proteins, highly homologous to the 5th and 6th TM segments of the VGKCs, sometimes duplicated in tandem (4TM) The structural diversity among 6TM, 4TM, and 2TM channels is also shown in the third line 6TM channel families (sharing amino acid sequence identity of about 25–30%) are shown in the fourth line, where they are classified on the basis of genetic and functional differences: classical VGKCs (Kv1, Kv2, Kv3, and Kv4), KCNQ (Kv7) channels, EAG channels (for ether‐a‐go‐go, the name of a Drosophila mutant; Kv10, Kv11, and Kv12), large‐conductance voltage‐ and Ca2+‐dependent K+ channels or BK (with a cytoplasmic domain mediating their regulation by [Ca2+]i), CNG channels (with a C‐terminal domain where cyclic nucleotides such as cAMP and cGMP bind to activate the channel), and small conductance Ca2+‐dependent K+ channels or SK The last line shows that, among these gene families, a large number of subfamilies exist (sharing an amino acid sequence identity of about 50–60%); these are mostly characterized by names of Drosophila mutants (“shaker,” shab,” “shaw,” “shal”) KCNQ‐type channels give rise to two important K+ currents: neuronal IKM (inhibited by muscarinic receptor activation) and cardiac IKs (responsible for the slow component of the ventricular repolarizing current IK) ERG channel subfamilies are instead responsible for IKr, the rapid component of the ventricular repolarizing current IK, also expressed in neurons Among Kir (inwardly rectifying) channels, the best known are ROMK1 (renal outer medullary kidney, involved in K+ cycling across epithelial cells of the kidneys and other tissues), IRK1 (the classical inward rectifier of cardiac and skeletal muscle), GIRK1 (an inwardly rectifying channel activated by G‐protein βγ‐subunits binding to the C‐terminus tail following GPCR activation), and KATP channels, regulated by [ATP]i (see Fig. 27.8) In subsequent years, this hypothesis has been tested and confirmed by mutagenesis, fluorescence spectroscopy, and electrophysiological experiments Over the last 15 years, crystallographic studies of bacterial and mammalian channels have provided a more detailed view of the role of S4 positively charged residues in the activation process However, the precise structural rearrangements occurring in the voltage sensor during activation are not fully understood yet, since structural results have been mostly obtained in the absence of transmembrane potential, thus in a “depolarized” 318 (a) ION CHANNELS (b) Transporter + Closed S5 – Sliding helix + Open – S3 + S4 S4–S5 S6 S3 S5 S4 S6 S4–S5 – PVP flexible region (c) – + Paddle + – – + Figure 27.5 Models of voltage sensing in voltage‐gated channels (a) Models of voltage‐sensing domain (VSD) movement during gating Gray cylinders represent S4 unless otherwise indicated Protein surrounding S4 is in light gray The first four S4 arginines are shown as dark spheres when they are in the foreground, as light spheres when they are behind the cylinder To keep drawings simple, in some of the models the arginines are arranged on the same face of the S4 helix In each model, the S4 resting position is shown on the left and the activated position on the right In the helical screw model, the extent of S4 transmembrane movement ranges from ~5 to ~13 Å, depending on the tilt of the helix (Modified from Ref [2]) (b) VSD movements are transmitted to the pore region The panel shows two models (closed state on the left, open state on the right) of the Kv1.2 channel The boxed region has been enlarged in panel c (c) Bottom view (from the intracellular side) of the Kv1.2 pore, showing the position changes of the C‐terminal part of S6 in the closed–open transition (Modified from Ref [3]) state of the membrane, when the voltage sensors are likely found in an activated state, whereas much less information is available on the “resting” state of the sensor Three main conceptual models have been proposed to describe the dynamic structural changes occurring in the voltage‐sensing domain during activation (Fig. 27.5a): •• The transporter model In this model, most S4 arginine residues are positioned within water‐accessible polar cavities, in direct contact with the intracellular or extracellular environment Upon membrane depolar ization (activation), S4 would mostly undergo rota tional movements, with an axial dislocation of about 2–4 Å S4 positive charges would therefore move from a cavity in direct continuity with the intracellular environment to one facing the extracellular space The transmembrane electric field would thus be concen trated in a narrow region of the protein, only 5–10 Å wide, considerably thinner than the plasma membrane (~30 Å) This model highlights similarities between the structural changes undergoing in the voltage sensor of VGICs and those occurring in transporters during ion translocation •• The “sliding helix” model According to this model, in the resting state, the positively charged S4 segment would be drawn closer to the intracellular region of the membrane by the electrostatic potential (negative inside); positive charges would interact with negative charges in the S1, S2, and S3 segments Membrane depo larization would cause a 60–180° rotation of S4, together with a 5–15 Å axial dislocation, to allow the first three arginine residues to completely cross the membrane electric field and to form novel electrostatic contacts with neighboring protein regions •• The “paddle” model This model is based on the tridi mensional structure of the KvAP bacterial channel, in Index clostridial toxin, 329, 475 clozapine, 15, 65, 71, 264, 490, 494, 516–18, 682 c-myc, 408, 637 CNS depressants, 124 co-activators, 245, 246–50, 254 coagulation factors, 116 cocaine, 12, 38, 123–4, 126, 321, 324, 338, 346, 361, 364, 366–8, 371–2, 374, 482–3, 486–7, 495, 512, 539, 544, 567, 584 codeine, 49, 57, 62, 260–261, 526, 573, 679, 684 coffee, 12, 562 cola, 562 colchicine, 94, 420, 474, 653 colistin, 642–3, 650 collagen, 42, 149, 205, 228, 300, 395, 399, 437, 597, 618 compound 48/80, 525 computer-aided drug design (CADD), 692 concanavalin A, 525 connexons, 465–6 conotoxin (α-), 502 constitutive androstane receptor, 272–83 drug metabolism, 283 contraception, 280 Contract Research Organization (CRO), 709 convertases, 386 endothelin convertase, 386 copy number variation (CNV), 257 co-regulators, 247–50 co-repressors, 246–50 CoREST, 249 corneal lesions, 559 corticotrophin releasing factor (CRF), 569, 570 receptors, 569, 570 cortisol, 64, 273, 280, 452–3 cortisone, 14, 61, 280 cotransmission, 567, 569 crizotinib (Xalkori), 214 cromakalim, 320, 335 crosstalk, 168 curare, 14, 501, 503–4, 506, 508 cyanoguanidines, 335 cyclic polypeptides, 642 cyclizine, 527 cyclooxygenase (COX), 461, 610–613 COX-1, 610–613 COX-2, 610–613 gene, 610 inhibition, 611–13 protein, 610–611 cyclophilin A (CypA), 436 cyclophilin D (CypD), 436 cyclophosphamide, 417, 626–30, 635 cyclopyrrolones, 534, 539 cycloserine, 642, 644–5 cyclosporin A (CsA), 15, 49, 71, 222, 253, 263, 353, 413, 436, 626–7, 629–30, 679–80, 682–3, 685 clinical use, 631 pharmacokinetics, 631 cylexin (CY-1503), 233 cyproterone acetate, 281 cysteine proteases, 380 cystic fibrosis, 136, 303, 306, 311, 314, 345–6, 387, 559–61, 600 cystine-glutamate exchanger, 544 cytarabine, 420 cytisine, 502–4 cytochrome c, 335, 384, 389–90, 409–11, 434–7, 596, 599–601, 605, 607 cytochromes p450 (CYPs), 62–5, 258–62 catalytic cycle, 63 cellular localization, 63 distribution, 68 drug interaction, 682 drug metabolism, 681 enzymes, 62–5 evolution, 64 families, 64 isoforms, 71 polymorphism, 67, 258–62 toxicity, 62, 72 cytokine receptor, 217–24, 235 agonistic effect, 238 antagonistic effect, 237 soluble, 235 soluble viral, 236 cytokines, 114, 220–224, 236–8, 637–8 adaptive immunity, 222–3 anti-inflammatory, 223 classification, 217 hematopoietic, 220 innate immunity, 220–222 pharmacology, 223–4 cytosine arabinoside (Ara-C), 419–20 cytoskeletal matrix, 117 cytoskeleton, 112, 117, 156, 159, 170, 198, 210, 227, 387, 473, 605 cytosolic 5’ nucleotidase, 555 dacarbazine, 416–17 daclizumab, 239, 628, 636, 695 dalcetrapib, 449–50 danazol, 281 danger signals, 553 dantrolene, 321 dapsone, 642 daptomycin, 642–3, 650 dasatinib, 233, 424 daunorubicin, 413, 416, 422–3 d-curarine, 525 death domain (DD), 410, 411 death effector domain, (DED), 409, 411 719 death receptors, 111, 115, 408 deltorphin, 574, 576 dementia, 86, 385, 483, 498, 504, 549, 550, 592 denufosol, 560–561 deoxyribo nucleic acid (DNA) polymorphisms, 266 topoisomerase inhibitors, 421–3 dependence, 121–9 clinical phenomena, 125 diagnostic criteria, 125 physical, 580, 582, 584 psychic, 7, 122–9, 583, 584 symptoms, 125 therapy, 128 deprenyl, 525–6 derived no effect level (DNEL), 674 dermorphin, 574, 576 desipramine, 35, 71, 338, 372 desogestrel, 280 dexamethasone, 49, 70, 187, 275, 280, 613, 630 dextran, 46, 525–6 dextromethorphan, 573 dextropropoxyphene, 574 diabetes insipidus, 192 diabetes mellitus, 14, 117, 150, 152, 170, 192, 202, 248, 282, 295, 298, 314, 320, 332–5, 391, 438, 440, 443, 446–7, 452–61, 695 diacylglycerol (DAG), 194, 196, 197 diacylglycerol acyltransferase, 445 inhibitors, 446 pharmacological/clinical activity, 446 diadenosine polyphosphates (APxA), 559–60 diamine oxidase (DAO), 521 diazepam, 14, 49, 57, 61–2, 83, 534–5, 539, 582 diazoxide, 320, 335, 437, 459 diclofenac, 71, 335, 611–13, 682, 710 diffusion, 23–6 facilitated diffusion, 26 simple diffusion, 24–5 through membrane channels, 26 digoxin, 32, 34, 57, 77, 79, 86, 93, 263, 347–9, 680–681, 683–6 dihydropyridines, 320–321, 326, 328, 330 diisopropyl fluorophosphate (DFP), 380, 500 dilazep, 556 diltiazem, 35, 49, 71, 263, 321, 325, 327, 330, 341, 343, 682–3 dimaprit, 527–8 dimethindene, 527 dipeptidyl peptidase-4 (DPP-4), 455 inhibitors, 459–60 diphenhydramine, 338, 506–7, 527 diphenoxylate, 573 720 Index dipivefrine, 492 dipyridamole, 556, 561 diquafosol, 559, 561 discovery alkaloid, 12 benzodiazepine, 14 glucosides, 12 penicillin, 14 vaccines, 13 disopyramide, 325, 338 dissociation constant, 96 distribution, 21, 45, 46–53 redistribution, 83 volume, 46, 48–9, 74, 81, 84 disulfide bonds, 136 disulfiram, 128–9, 682 diuretics, 8, 15, 56, 100 101, 280, 320–321, 347, 356, 357, 461, 679–80, 685–6 dobutamine, 331, 492 dofetilide, 325, 337–8 dolasetron, 516–17 Domagk, G., 13 domoic acid, 549 donepezil, 500, 505 dopamine, 125–7, 190, 492, 512, 514–15, 518, 582–3 dopaminergic receptors, 488 agonists in cardiogenic shock, 493 agonists in disorders of the CNS, 494 dopaminergic agonist, 461 dopaminergic antagonist, 494 D2 receptor, 190, 192, 195, 198 drugs, 493–4 dopaminergic system, 481–3 distribution, 481 dopamine and behavioral disorders, 482 dopamine on the ctz, hypothalamus and pituitary, 483 dopaminergic nigrostriatal system and movement control, 482 functions in the CNS, 482 dopamine transporter (DAT), 126, 360–361, 370–371 pharmacology, 371 dose, 74 absorbed, 74–5, 78 age, 84–7 attack dose, 80 dosage corrections, 84–7 dosing interval, 79 hepatic pathology, 86 loading dose, 80 maximal tolerated dose (MTD), 669–70 multiple, 77–8 renal pathology, 86–7 dose-response curves, 99–102 doxazosin, 492 doxepin, 338, 527 doxorubicin, 42–3, 263, 413, 416, 422–3 doxycycline, 642 droperidol, 338, 494 droxicam, 612 drug, 4, 93 acidity constant (pKA), 24 affinity, agonist, allosteric, agonist inverse, 6, 109 agonist partial, antagonist, biological, 5, 16, 694 biosimilar, competition, 6, 99 concentration(s), 5, 27, 46, 48, 50, 59, 78–9, 86, 418 dependence (see dependence) development, 689–99, 700–713 clinical, 708–13 diagnostic tests, 713 failure rate, 709, 712 process, 15, 16 discovery, 700–703 generic, 4, 5, 612, 691–2, 694, 706 herbal, industries, 12, 13, 17 interactions, 611, 678–86, 705–6 dietary supplements/components, 685 grapefruit juice, 683 herbal medicine, 685 pharmacodynamic, 684 pharmacokinetic during absorption, 679 pharmacokinetic during biotransformation, 681 pharmacokinetic during distribution, 681 pharmacokinetic during excretion, 683 metabolism, 24, 59, 61–72, 258, 283, 673, 678, 681–2, 700–707 conjugation, 34, 58, 62, 66–8, 258, 634, 703–4 extrahepatic methabolism, 68 genetic polimorphisms, 258 inducers, 70 induction, 59, 65, 69–70, 679, 681–5, 695 inhibition, 71–2 inhibitors, 71 intestinal flora, 69 phase I, 62 phase II, 62, 66 phase II enzymes, 262–3 phase II enzymes-polymorphisms, 262–3 phase II enzymes-polymorphismsclinical effects, 264 site, 68–9 therapeutic relevance, 72 names, orphan, 698 potency, research (R), 691–2 selectivity, target, 93 tolerance, 118 drug metabolism and pharmacokinetics (DMPK), 700–707 in vitro, 700–707 in vivo, 700–707 drug response, genetic variability, 256–7 drugs approved per year, 709 drugs of abuse, 124 entactogens, 124 hallucinogens, 124 psychostimulants, 124, 486–7 sedative hypnotics, 124 dry eye syndrome, 561, 563 dynorphin, 567, 570, 572, 574–6, 578, 582, 584 dyslipidemia, 282, 439–51, 591 echinocandins, 651 ecothiopate, 500 ecstasy (MDMA), 124, 126, 361, 366, 485, 515 ectonucleotidases, 555–6 ecto-ADPase, 555 ecto-ATPase, 555 edrophonium, 499–500, 505 efalizumab (Raptiva), 233, 628, 636 efavirenz, 655, 660 efficacy, 100, 103, 108 theory, 104 EGFR see growth factor receptors eicosanoids, 190, 608–20 epoxyeicosatrienoic acids, 608, 615–17 hydroxyeicosatetraenoic acids, 608, 615–17 isoeicosanoids, 608, 617–18 isoprostanes, 608, 617–18 leukotrienes, 608, 615–16, 620 prostanoids, 608, 610–614 receptors, 618–19 eletriptan, 517 elimination, 22, 53 rate constant, 40, 53 time constant, 74 elongation factors, 646 empathogens, 124 enalapril, 387, 567 encainide, 325 endo-adenosine deaminase, 555 endocannabinoids (ECs), 586–95 transporter, 288 Index endocannabinoid system (ECS), 585–95 anxiety and depression, 591 biological function, 588–93 cancer, 592 eating disorders, 590 immune system, 592 neurodegenerative diseases, 592 pain and inflammation, 591 synaptic plasticity, 589 endocytosis, 23, 25–6, 116, 161, 198, 232, 360, 383, 439, 456, 471, 475, 582, 654 endomorphins, 574–6 endonuclease G, 411 endoplasmic reticulum (ER), 62, 63, 65, 66, 117, 135, 139, 142, 157, 339, 346, 352, 353, 380, 382, 383, 385, 409, 426, 442, 450, 484, 535, 538, 566, 568, 571, 610 endoprotease, 396 endorphins, 94, 567, 572 β-endorphins, 567 endosomes, 25, 115, 145, 161, 199, 290, 360–361, 372, 381, 471 endothelin, 158, 381, 386–7 enhancer, 246 enkephalins, 29, 94, 501, 510, 562, 565, 570, 572, 574–5, 578 entactogens, 124 entecavir, 659 enteramine, 509 enterochromaffin-like cells (ECL), 521 entero-hepatic cycle, 58 enzymes generating lipid second messenger, 210–211 ephedrine, 485, 492 epibatidine, 502, 504 epigenetic modulators, 426 demethylating agents, 426 HDAC inhibitors, 426 non-coding RNA, 426 epipodophyllotoxins, 416, 423 epirubicin, 416, 422–3 epoxide hydrolases (EH), 62, 64 epoxomicin, 426 equilibrium, 95–6 conditions, 96 constants, 95 ERK, 147–8, 413, 581, 583 cascade, 151–2 ERK5, 150 Erlich, 13 erlotinib (Tarceva), 152, 212, 214–15, 416, 424, 426 erythroidine (β-), 502–3 erythromycin, 14, 34, 71–2, 263, 338, 642, 647, 679, 682–5 escitalopram, 515, 517 esmolol, 325, 492 estradiol, 71, 167, 277–80, 681 estrogen receptors, 272–80 agonists, 280 antagonists, 280 indication, 281 selective estrogen receptor modulators (SERMs), 281 estrogens, 42, 58, 264, 271, 272, 277, 280, 446, 498, 523, 672, 679 estrone, 280 etanercept, 627, 636, 695 etaracizumab (Abegrin), 233 ethacrynic acid, 56, 347, 357, 617 ethanol, 62, 64–5, 69–70, 100, 123–4, 126, 128, 350, 533–4, 537, 539–40, 631, 682 ethanolamine, 530, 587 ethics committee, 709 ethinyl estradiol, 280, 681 ethosuximide, 320, 327, 331 ethylenediamine, 527 ethylephrine, 492 etodolac, 612 etofibrate, 440 etoposide, 416, 422–3 etoricoxib, 611–13 etretinate, 282 European Chemical Agency (ECHA), 675 European Food and Safety Authority (EFSA), 675 European Medicines Agency (EMA), 691, 708 excipient, 4, 32, 36, 73 excitotoxicity, 146, 547–9 excretion, 55–9 hepatic, 58 renal, 55–8 exocytosis, 23, 140, 168, 360, 411, 439, 454, 455, 467, 470–471, 475, 514, 568 exon skipping, 286–7 extracellular matrix, 46, 114, 211, 225, 228, 384, 395, 466 extracellular protease, 395 antagonists, 399 inhibitors, 399 extraction index, 54–5 factor(s) general transcription (GTF), 243 inducible, 251–2 transcription, 243–6, 251–2 FADH2, 435 FAK, 230 famciclovir, 654 famotidine, 527–8 fampridine, 505 farnesoid X receptor, 272–82 farnesyl pyrophosphate synthase inhibitors, 441–2 721 farnesyltransferase, 157 Fas-associated protein with death domain (FADD), 410–411 Fas/FasL, 13, 410, 411 fatty acid biosynthesis, 440, 443–4 desaturases inhibitors, 444 synthase inhibitors, 443–4 pharmacological activity, 444 feed-back loops, 170 felodipine, 327, 330 fenamates, 335, 612 fenfluramine (feh), 366, 370, 513 fenofibrate, 71, 440 fenoldopam, 104, 490 fenoprofen, 612 fenoterol, 492 fentanyl, 573, 582 fexofenadine, 263, 527 F0F1 ATP synthase, 436 fibrates, 70, 282, 438, 440, 447, 679, 684 pharmacological activity, 447 fibrinogen, 228–9, 233 fibronectin, 115, 205, 217–18, 228–9, 233, 395–400 Fick’s law, 24 first-pass effect, 35, 58 FK-506, 71, 222, 253, 263, 338, 627, 630–633, 679–80, 682 flavin monooxygenases (FMO), 62–3 flecainide, 71, 325 Fleming, 14 fluconazole, 71, 682 flucytosine, 651, 654 fludarabine, 419 flufenamic acid, 612–13 fluoromethylhistidine (α-FMH), 521, 523, 525–6 fluoro-oxindoles, 335 fluorouracil (5-FU), 35, 262, 419–20, 653 fluoxetine, 71, 366, 370, 486, 514–15, 517 fluoxymesterone, 281 flupirtine, 320, 335, 339 flurbiprofen, 611–13 flutamide, 281 fluvastatin, 71, 440 fluvoxamine, 71, 514–15, 517, 682 flux-to-volume ratio, 27, 52 folic acid, 58, 288, 418–19, 541, 629, 642, 649 follicle-stimulating hormone (FSH), 42, 190–191, 481 fomivirsen, 654 Food and Drug Administration (FDA), 128, 132, 138, 152, 214, 256, 263, 299, 303, 388, 443, 451, 590, 592, 656, 658, 672, 691, 696–7, 704, 706, 708–9 formoterol, 492 722 Index foscarnet, 656 frovatriptan, 517 furin, 386–7, 393 furosemide, 49, 56–7, 101, 347, 357–9, 532 fusidanes, 642 fusidic acid, 642, 648 GABA see γ-aminobutyric acid (GABA) GABA-α-ketoglutarate transaminase, 530 GABAergic transmission, 529–40 gabazine, 531, 533 galantamine, 500, 505 Galen, 8, Galileo Galilei, 11 γ-aminobutyric acid (GABA), 190, 470, 512, 529–31 distribution, 529 metabolism, 530 receptor GABAA, 531–5 GABAA extrasynaptic, 533–4, 537, 539 GABAA subtypes, 532–4 GABAB, 190, 192, 537–9 release, 530–531 reuptake, 530 synthesis, 530 transporters, 367 pharmacology, 369 structure, 368 ganaxolone, 536 ganciclovir, 655–6 ganglioplegic, 504, 506 gap junctions see junctions GAPs, 158, 164 gastric parietal cell, 350 gastric secretion, 350 G-coupled cholecystokinin-B receptor (CCKB/gastrin receptor), 524 GDIs, 159 gefitinib (Iressa), 214–15, 416, 424 gemcitabine, 416, 419–20 gemfibrozil, 71, 282, 440, 447, 682 gemtuzumab, 239, 695 gene delivery, 305 generic(s) see drug gene therapy, 43, 262, 284, 295, 303–6, 303–6 ex-vivo, 304 in-vivo, 304 genetic polymorphisms, 258 clinical effects, 258 drug pharmacokinetics, 258 genomics, 694 gentamicin, 57, 642, 647, 685 gepirone, 516–18 geranylgeranyltransferase, 157 gimatecan (ST1481), 421–3 glial cells, 28, 202, 324, 362, 368, 466, 471, 472, 530, 535, 541, 543, 603 gliflozins, 458 glinides, 332–3, 455, 458–9 glomerular filtration, 82, 84–5, 446, 479, 557, 603, 609, 632 glucagon, 106, 190, 343, 452–4, 458–60, 563 glucagon-like peptide-1 (GLP-1), 351, 454, 458–60 glucocorticoid receptor, 269–278 agonists, 278 regulated genes, 278 selective agonists, 278 glucocorticoids, 110, 221–3, 269, 278, 370, 609, 618, 632, 679, 684, 6268 mechanism of action, 632 resistance, 280 undesired effects, 276 glucose, 157, 162, 167, 169, 231, 280, 282, 321, 332–4, 350, 438, 440, 446–8, 452–61, 467, 478, 480, 491, 493, 497, 499, 513, 541, 551, 559–60, 563, 586, 599, 605, 634, 652 control, 452 intestinal absorption, 460 modulation of GLUT4 activity, 456 phosphorylation, 454 transport, 452 transporters (GLUT), 453–4 uptake, 452 glucosidase (α-), 460 glucosides, discovery, 12 glucuronidation, 66 glutamate (glutamic acid), 190–191, 470, 512, 541–52 metabolism, 541–2 synapses, 543–5 synthesis, 541–3 transport, 542–4 glutamate decarboxylase (GAD), 529–30, 539–40, 542 glutamate dehydrogenase, 542 glutamate receptors, 544–9 ionotropic, 545–6 AMPA receptors, 469, 544–6, 550, 604 kainate receptors, 43, 545–6 NMDA receptors, 117, 129, 141, 469, 545–7, 549–50, 604 ionotropic agonists, NMDA, 523 metabotropic agonist, ACPD, 548 metabotropic receptors (mGluRs), 190, 192, 198, 546–7 glutamate transporters (EAAT), 361–2 distribution, 352 function, 352 pharmacology, 363 substrates, 364 glutaminase 542 glutathione coniugation, 68 glutathione peroxidase, 434 glycemic control, 452–61 mechanisms, 452–7 pharmacology, 457–61 glycine receptors, 111, 175 glycopeptides, 642, 645, 648 glycosylation, 135, 138 inhibitors, 138 glycosylphosphatidylinositols, 137 Golgi apparatus, 117, 135, 143, 156, 157, 163, 380, 383, 385, 566, 599 Good Clinical Practices (GCP), 696, 708–9 Good Laboratory Practices (GLP), 672, 696 Good Manufacturing Practices (GMP), 697 G-protein-coupled receptor kinase (GRK), 192, 194 G-protein-coupled receptors (GPCRs), 189–201, 521, 555, 557, 559, 565, 568 dimerization, 192 effectors pathways, 195–8 GPR17, 559 G-protein-independent signaling, 199–200 interacting proteins, 198–200 AKAP, 198 β-arrestin, 192, 199–200 Homer, 198 NHERF1, 200 RAMP, 199 RGS, 198 ligand binding site, 191 mutations, 192 polymorphisms, 192 structural organization, 190–192 G proteins, 192–5 activation/inactivation cycle, 193 βγ complex, 193–7 effectors, 194–5 regulators of G protein signaling (RGSs), 193 α-subunits, 193–7 modification by toxins, 194 mutations, 194 Graft Versus Host Disease (GVHD), 626–7, 629, 631 granisetron, 338, 516–17 granulocyte colony-stimulating factor (G-CSF, filgrastim), 218, 220–221, 637–9, 694–5 granulocyte-macrophage colonystimulating factor (GM-CSF), 217–8, 220–221, 237, 634, 637–9, 694 grapefruit juice, 682–3, 686 Index grepafloxacin, 338 growth factors, 203 epidermal (EGF), 26, 113, 116, 151, 154–5, 168, 202–3, 205, 207, 218, 236, 275, 397, 428, 610, 637 nerve growth factor (NGF), 113, 151, 167–8, 171, 202–3, 205–6, 498 receptors, 202–16 activation and signal transduction, 205–13 epidermal growth factor receptor (EGFR), 203–5, 207, 214–15, 424, 427–8, 661, 691 functional domains, 204–5 molecular structure, 204–5 target for anticancer drugs, 215 vascular endothelial growth factor (VEGF), 150, 203, 207, 214–15, 254, 417, 428–9, 571 GSKβ3, 169, 170 guanabenz, 492 guanfacine, 492 guanine nucleotide exchange factors (GEFs), 158, 163 guanylyl cyclases, 604, 607 half-life (t1/2), 38, 40, 53–4, 75, 77 hallucinogens, 124 halofantrine, 338 haloperidol, 71, 108, 337–8, 494, 517 halothane, 62, 65, 321, 540, 682 Harvey, 11 hazard identification, 666, 669, 673 heart failure, 117, 251, 264, 269, 282, 342, 347–9, 492–3, 560, 602, 678 heart preconditioning, 560 heart rate, 196, 320, 342, 354, 479, 489, 491, 493, 507, 561, 579 hemicholinium (HC3), 499 heparin, 42, 49, 203, 228, 290, 521, 525, 585 hepatitis c, 429, 657 heroin, 61, 124, 483 hexamethonium, 57, 112 hexokinase, 437, 454 high production volume (HPV), 675 high-temperature requirement A (HTRA), 388 high throughput screening (HTS), 690 Hippocrates, histamine (2-(imidazol-4-yl)ethylamine), 28, 190, 520 [3H]-histamine, 526, 527 histamine-N-methyltransferase, 521 histamine receptors antagonists (antihistamines), 14, 263, 338, 483, 520, 527, 680, 684 H1R, 521 H2R, 520 H3R, 521 H4R, 520–526 H2R agonists, 528 H4R agonists, 527, 528 H4R antagonists, 527, 528 H2R selective antagonists, 527, 528 histaminergic neurons, 523 histaminergic transmission, 520–528 histidine-decarboxylase (HDC), 520 histone acetyltransferase (HAT), 248 histone code, 249 histone deacetylase (HDAC), 248–9 histones, 135, 148, 248, 274, 418, 425 HIV, 392 H+/K+ ATPase, 349–51, 523 gastric pump, 350 inhibitors, 347, 351 pharmacology, 350 structure, 350 HMG-CoA reductase inhibitors see statins homatropine, 506–7 hormone replacement therapy, 278 hormones, 190, 191 Human Genome Project, 691, 694 Huntington’s chorea, 562 hydralazine, 34, 262 hydrocortisone, 38, 62, 187, 634–5 hydrogen peroxide, 433 hydrolysis, 65 hydromorphone, 573 hydroxitriptamine see serotonin hydroxybutyric acid (γ-) (GHB), 539 hydroxyindolacetaldehyde, 513–14 hydroxyindoleacetic acid (5-HIAA), 511, 514 hydroxylation, 135 hydroxyl radical, 433 hydroxytryptophan (5-OH-tryptophan), 513 hydroxyzine, 338 hyperlipidemia, 444, 447, 459, 632 hypertension, 561 hypnotics, 56, 124 hypoglycemia, 453 endocrine response, 453 hypoglycemic drugs, 332, 458 hypothalamic–pituitary–adrenal (HPA) axis, 513 hypoxia, 553–4, 562 ibuprofen, 71, 612–3 ibutilide, 325 ICAM-1, 636 idarubicin, 416, 422–3 If current, 196 imatinib mesylate (Gleevec), 212, 214, 233, 263, 416, 423–4 imetit, 527, 528 imidazole-N-methyltransferase, 525 imidazopyrazines, 335 imidazopyridine, 532–5, 539 723 imipenem, 642, 685 imipramine, 49, 57, 61, 71, 369–70, 486, 515, 682 immepip, 527–8 immune cells, 558, 564 immune system, pharmacological modulation 625 immunoadiuvants, 639 immunomodulators, 114, 630, 636, 638, 657 immunostimulant drugs, 625, 637–9 immunosuppressive drugs, 187, 222, 224, 296, 338, 625–37 implitapide, 450 impromidine, 527–8 incretin effect, 454–5 incretins, 458–60 indacaterol, 492 indinavir, 71, 263, 387, 393, 682–3, 685 indobufen, 612 indomethacin, 57, 71, 612 inflammation, 511 infliximab, 239, 627, 636 inosine, 555, 629 inositoltrisphosphate (IP3), 194, 196, 198 receptor, 143–4 insulin, 16, 25, 31, 36, 42, 113, 117, 136, 150, 157, 170, 203–6, 275, 282, 320–321, 327, 331–3, 335, 389, 393, 444–5, 447–8, 454–61, 493, 557, 559, 563, 566, 591, 600, 603, 684–5, 685 exocytosis, 454 IR tyrosine kinase, 457 modulation of signaling, 459–60 receptor (IR), 454–5 resistance, 461 secretion, 455 integrase inibitors, 655, 660 integration of receptor signaling, 166–71 integrins, 114, 226–8 activation, 229 ligands, 290 signal transduction, 229–32 FAK, 230 Src, 230 interactions drug–diet, 686 drug–drug, 63, 108, 641, 678–86 pharmacodynamics, 684 pharmcokinetics, 678 interferons (IFNs), 114, 218, 236, 637–8, 657, 694–5 interferon α (IFNα), 17, 218, 236–7, 629, 638–9 interferon β (IFNβ), 17, 42, 71, 114, 236–7, 280, 599, 637, 638, 657, 694–5 interferon γ (IFNγ), 218, 222–4, 236, 597, 599, 605, 627, 630, 638–9 724 Index interleukins, 5, 114, 217, 389, 637, 639 IL-1, 236–7, 290, 380, 409, 599, 609, 637 IL-2, 17, 115, 243, 637, 694 IL-3, 114, 217, 638 IL-5, 217 IL-6, 115, 217, 220–223, 237–9, 290, 560, 627–8, 636 IL-7, 217–20, 237, 637 IL-10, 114 IL-18, 237 IL-22, 114 intestinal natriuretic peptide, 114 intetumumab (CNTO-95), 233 intracellular receptors, 6, 110 activating functions, 274–7 classification, 268, 272 DNA binding, 272, 274 drugs and indications, 271, 278–83 hormone responive element (HRE), 269 ligand binding domain, 272 ligand binding pocket, 272 ligands, 274–7 nomenclature, 272 regulation of gene expression, 272–7 specificity of action, 278 intrifiban (Integrilin, eptifibatide), 233 intrinsic activity, 104 inulin, 56, 85 iodofenpropit, 526–7 iodoprossifan, 526 iodoxuridine, 656 ion channels, 175–88, 311–59, 468 anionic channels, 339 cationic channels, 339 classification, 312 function, 312 gating mechanisms, 312 current-voltage relationship, 315 ligand-gated, 111, 113, 175–88, 312, 501, 568 rectification process, 315 structure, 316 voltage-dependent anionic channels (VDAC), 411, 436 ionophores (A23187, X527A), 525 ipilimumab, 239 ipratropium, 506 ipsapirone, 514, 516–17 iPS cells, 298 irinotecan (SN38), 262–3, 266, 416, 421–2, 429 UGT1A1 polymorphisms, 263 ischemia, 555, 560, 562 isepamycin, 642, 647 isoflurane, 321, 336, 537, 540 isoniazid, 146, 262, 530, 682 isoprenaline, 57, 338 isoproterenol, 34–5, 57, 265, 487, 491–3 isosorbide, 597, 606 isotretinoin, 282 ivabradine, 196, 321, 341–3 ivermectin, 353 JAK2 tyrosine kinase, 200 JNJ7777120, 526–7 JNK, 147–8, 152–3, 413 josamycin, 642 junctional epidermiolysis bullosa (JEB), 306 junctions adherent, 56–7, 226, 232 desmosomes, 232 gap, 465–6 neuromuscular, 111, 116–17, 176, 180, 328, 475, 497, 501–2, 508 thigh, 32, 232 kanamycin, 49, 642, 647 kernicterus, 51 ketamine, 43, 124, 126, 549–50 ketanserin, 338, 491, 516–17 ketoconazole, 71, 263, 280, 338 ketoprofen, 612 ketorolac, 612 kidney, 55–8 kinetic constants, 96 kinetics first-order, 25, 38–41, 74 multicompartmental, 81–82 zero-order, 38 kiss and run, 471 kurtoxin, 327 labetalol, 35, 492 lactacystin, 387, 426 lactams (β-), 642, 645 laminin, 228 l-amino acid decarboxylase (AADC), 524 lamivudine, 655, 659 lamotrigine, 320, 325 Langmuir isotherm, 97 lapaquistat, 440, 443 lapatinib, 214–15 latrotoxin (α-), 475–6 Lavoisier, 11 law of mass action, 99 l-DOPA, 29, 34, 494, 681, 683 lead compound, 692 lead optimization, 701–3 lectins, 525 lenalidomide, 627, 630 Leroux, 12 leukocytes, 225, 227–9, 231 recruitment, 225, 227, 233 leukotrienes, 608, 615–17, 620 LTA4, 615, 616 metabolism, 616 LTB4, 615 LTC4, 615 LTD4, 615 leukotrienes receptors, 620 levcromakalim, 335 levobunolol, 492 levofloxacin, 263, 338, 642 levorphanol, 573 lidocaine, 35, 320, 325 lifetime, 40 ligand binding domain, 179, 272, 544–5 lincomycin, 642–3 lincosamids, 642, 648 linezolid, 642, 648, 650 linopirdine, 320, 337 lipid conjugation, 133, 288, 290 lowering drugs, 439–51 metabolism transcriptional control genes, 446 modifications, 136 rafts, 117 transfer proteins, 448 lipofectin, 287 lipooxygenase, 608–9, 615–17 inhibitors, 616 5-lipooxygenase, 609, 615–16 12-lipooxygenase, 609, 616 15-lipooxygenase, 609, 616 pathway, 615 lipopeptides, 642 liposomes, 43, 287 lithium, 14, 34, 57, 197–9, 338, 680, 684 liver, 58–9 liver X receptors, 446–8 regulated genes, 446–8 synthetic ligands, 446–7 lomitapide, 450 long-term potentiation (LTP), 558, 561 loop diuretics, 347 loperamide, 263, 573 lopinavir, 387 loratadine, 527 lovastatin, 440 l-tryptophan, 513–14, 518 lumiracoxib, 611–13, 710 luteinizing hormone (LH), 25, 126, 190–192, 481, 489 receptor, 190–192, 195 lysergic acid (LSD), 124, 512, 516–17 lysophosphatidic acid, 190 lysosomal proteases, 382 lysosomes, 117, 135, 198, 290, 361, 372, 380, 382–3 macrolides, 338, 642, 647 macrophages, 558 Magendie, 12 magic mushrooms, 124 Malpighi, 11 Index mapirocin, 642, 648 maprotiline, 366 margin of exposure, 668, 675 mastocytes, 558 MDR1/MDR2, 263, 283, 346 mecamylamine, 501, 504, 506 meclizine, 527 meclofen, 335 meclofenamate, 335, 612 mediator, 246 medroxyprogesterone acetate, 280 mefenamic acid, 612–13 MEK, 152 melanocyte-stimulating hormones (MSH), 567–9 melatonin, 511, 513–14 meloxicam, 612 melphalan, 417–18 memantine 43, 549–50 membrane permeability, 701 membrane transporters, 345–58 clinical use, 347 memory, 122, 127 menopause, 279 meperidine, 65, 573 mepyramine, 526–7 mercaptopurine, 262, 416, 419 meropenem, 642 mesangioblast, 299 mescaline, 124 mesocorticolimbic system, 125–7, 583 meta-analysis, metabolites metabolites in safety testing (MIST), 704 reactive, 704 metalloprotease, 381, 399–401 cancer, 398 cancer cell migration, 399 cell migration, 398 matrix metallo protease (MMP), 396, 400 membrane metallo protease inhibitors, 399 metastasis, 397, 399 tissue inhibitors of metalloproteases (TIMP), 398 tissue remodeling, 396, 399 metformin, 282, 438, 458–9 methacholine, 504, 506, 507 methadone, 124, 128–9, 573 methamphetamine, 124, 370, 373, 485 methotrexate, 257, 416, 418–19, 629, 636, 679–81, 684 methylation, 67, 136 methyldopa, 484, 492 methylhistamine, 525, 527 methyllycaconitine, 502 methylphenidate, 372, 485 methyltestosterone, 281 methylxanthine, 341, 343, 553, 562–3 methysergide, 517 metilfenidate, 366 metipranolol, 492 metoclopramide, 34, 483, 494, 517, 680 metoprolol, 34–5, 49, 108, 325, 492 metrifonate, 500 metronidazole, 643 mevalonate pathway, 437 441 mexiletine, 320, 325 mianserin, 527–9 Michaelis–Menten equation, 97 microglial cells, 558 microRNA (miRNA), 285 microsomal triglyceride transfer protein (MPT), 450 inhibitors, 450–459 microtubule(s), 232, 413, 416, 420, 652 acting drugs, 420 taxanes, 420 vinca alkaloids, 420 midodrine, 492 mifebradil, 320, 325, 338 mifepristone, 280 mineralcorticoid receptor, 272 antagonists, 280 mineralcorticoids, 110, 272, 280 minocycline, 642 minoxidil, 320, 335 miokamycin, 642 mirabegron, 488, 492 miravirse, 658 mirtazapine, 486, 517 misoprostol, 615, 619 mitochondria, 143, 413, 433–8 permeability transition pores (PTPs), 411, 435–7 reactive oxygen species (ROS), 411, 433–8 mitochondrial drugs, 437–8 antineoplastic agents, 437 antioxidant, 437 mitochondrial dysfunction, 437 mitochondrial metabolism, 437–8 mitochondrial membrane potential (MMP), 411, 433, 437 mitochondrial translocator protein, 437 Mitogen activated protein (MAP), 630 Mitogen activated protein kinases (MAPK), 133, 147–53, 195, 199, 576, 577, 581, 582, 583 pharmacological inhibitors, 151–3 specificity, 150–151 subtypes, 147–50 mitoxantrone, 416, 422–3 molecular modeling, 692–3 monoamine oxidase (MAO), 370, 434, 521 MAO A, 511, 513–4, 518 MAO B, 525 725 monoamines transporters, 364–7, 371–2 antidepressants, 372 distribution, 366 function, 372 pharmacology, 366 structure, 372 substrates, 366 monobactams, 642 moricizine, 325 morphine, 57, 124, 126, 573 morpholines, 654 mosapride, 518 moxifloxacin, 642 mTOR, 169, 170 mucins, 225–8 multidrug resistant associated proteins, 26, 658 multiple sclerosis, 233, 280, 302, 320, 336, 505, 521, 539, 553, 590–599, 627, 635–7, 638 mupirocin, 642, 648 muromonab-CD3, 627, 635, 695 muscarine, 501, 504, 507 muscarinic toxins (MT), 503, 504 muscimol, 531, 537 muscular dystrophy, 295, 387, 563 Becker muscular dystrophy (BMD), 301 Duchenne muscular dystrophy (DMD), 286, 301, 600, 602, 605–6 myasthenia gravis, 117, 500, 505, 626–7 mycophenolate mofetil, 627, 629, 679 myocardial infarction, 437 myristoylation, 136 nabumetone, 612 Na+/Ca2+ exchanger (NCX), 346, 353–6, 353–6 pharmacology, 354 properties, 354 structure /distribution, 353 N-acetyltransferases (NAT), 67 NADH(H+), 435 Na+/H+ exchanger (NHE), 346, 355–6 pharmacology, 356 structure, 355 Na+/H+ exchanger regulatory factor (NHERF1), 200 Na+/K+ ATPase, 346–9 operation mode, 349 pharmacology, 348 structure, 348 Na+/K+/Cl-cotransporter (NKCC), 356–8 pathology, 357 pharmacology, 358 structure, 357 nalbuphine, 573 nalidixic acid, 642, 649 naloxone, 129, 574, 580, 684 naltrexone, 128–9, 574 726 Index namitecan (ST1968), 421 nanodrugs, 18 nanomedicine, 43 nanotube, 466 naphazoline, 492 naproxen, 71, 606, 611–13 naratriptan, 517 natalizumab (Tysabri), 233, 628, 636, 695 nebivolol, 492–3 necrostatin-1, 413 nelfinavir, 71, 387, 393, 693 neomycin, 14, 642, 647 neostigmine, 35, 49, 500, 503 neprilysin, 381, 386–7 nerve growth factor (NGF) see growth factor netilmycin, 642 neurexins, 473 neuroadaptation, 121–3, 126–7 neuroligins, 473 neuromuscular blockers, 504, 506 neuromuscular junction see junctions neuropeptides, 468–9, 565–71 colocalization, 367 encoding genes, 566 functions, 569 neuropeptide Y (NPY), 567–70 processing, 566–7 receptors, 567–8 secretion, 567–8 storage, 567–8 synthesis, 566–7 therapeutic potential, 569 neuropharmacology, 474 neurosteroids, 533–4, 536, 540 allopregnanolone, 536, 540 tetrahydrodeoxycorticosterone (THDOC), 532, 540 neurotensin, 482, 525, 571 neurotoxins, 168, 475–6 neurotransmitters, 6, 57, 93, 94, 111, 113, 122, 175, 177, 186, 190, 194, 321, 331, 361–60, 417, 465–72, 475, 484, 500, 522, 538, 553, 561, 567–8, 604, 608 receptors, 468 transporters dependence from ions, 362 family evolution, 367 H+-dependent, 372–3 Na+/Cl−-dependent, 364–72 Na+ K+-dependent, 361–4 structure and function, 362 neutral amino acid transporter, 513 nevirapine, 655, 660, 705 NF-kB, 251, 410, 428, 632 nicorandil, 335 nicotinamides, 335 nicotine, 124, 126, 501, 503–4 replacement therapies, 128–9 nifedipine, 35, 49, 71, 326–5, 682–3 nikkomycins, 651–2 nilotinib, 424 Nim 811, 436 nimesulide, 611–13 nimotuzumab, 239 nipecotic acid, 365, 368, 374 nitric oxide (NO), 497, 511, 516, 523, 561 atheroscelrosis, 602 biochemistry, 599–602 biosynthesis, 597–9 NO synthases, 597–9 NO synthases control by NO, 599 cardiovascular system, 602–3 central and peripheral nervous systems, 603–4 cytochrome c oxidase inhibition, 600–601 guanlyate cyclase activation, 599–600 hypertension, 602 and immune system, 605 metabolic diseases, 603 metabolic syndrome, 603 microRNAs, 602 nitrates tolerance, 606 nitrate vasodilators, 606 nitric esters, 606 pharmacology, 606–7 respiratory system, 603 skeletal muscle, 604–6 S Nitros(yl)ation, 601–3 stimulators of cGMP action, 606 systemic and organ effects, 602–606 nitrofurans, 643 nitrofurantoin, 643 nitroglycerin, 35, 38, 42, 49, 57, 597, 602, 606 nitroimidazoles, 643 nizatidine, 527, 528 NMDA receptors see glutamate receptors N-methylhistamine, 521 N-methylimidazoleacetic acid, 521 N,N,diethyl-2-[4-(phenylmethyl) fenoxiletanamine] (DPPE), 523 nociceptin, 572, 574, 575 nociception, 558 nocodazole, 474 noncholinergic, nonadrenergic (NANC), 553 nonsteroidal anti-inflammatory drugs (NSAIDs), 611–13 adverse effects, 611, 613 coxibs, 611–13 therapeutic activities, 611, 613 traditional, 611–13 noradrenaline, 156, 360, 366, 371, 471, 478, 484–5, 492, 514, 517, 567 norfloxacin, 642, 680 norgestimate, 280 nortriptyline, 57, 259, 515, 517–18 Nuclear Factor of Activated T lymphocytes (NF-AT), 251 nucleosides, 553 nucleosome, 246 nucleotides, 553 cyclic, 176, 178, 179, 183, 317, 339, 341 nucleus basalis of Meynert, 495 observational studies, 710 occupancy theory, 101 threshold, 107 ocular dryness, 559 oil-water partition coefficient, 24, 32 olanzapine, 516–18 oligonucleotides, 285–91 antisense, 286 delivery, 287 inhibition of miRNA, 286 LNA, 286, 289 2’-O-Alkyl-ribonucleotides, 289 pharmacokinetics, 289 pharmacotoxicology, 289–90 phosphoroamidates, 289 phosphorotioates, 289 PNA, 289 structure, 288 toxicology, 289–90 omalizumab, 628, 636 omeprazole, 15, 70, 71, 259, 347, 351, 682, 685 ondansetron, 71, 263, 338, 517 operant conditioning, 123 opiates, 124, 126, 190, 573 addiction, 583 endogenous peptides, 572 endogenous peptides distribution, 574 opioid receptors, 575 cardiovascular effects, 579 distribution and effects, 576–80 effects on food intake and body temperature, 580 effects on GI tract, 579 effects on immune system, 580 GPCR, 575–6, 580, 582, 584 modulation of nociceptive transmission, 576 NOP, 575, 584 respiratory depression, 579 signal transduction, 575 opioid system, 572–84 organic nitrates, 35 organic phosphates, 338 ornithine transcarbamilase (OCT) deficiency, 304 Index orthosteric, 102–3 binding sites, 103 ligands, 102 oseltamivir, 656, 657 osteoblasts, 513, 563 osteoclasts, 384, 563 o-sulfate, 514 oxaliplatin, 416, 418 oxandrolone, 281 oxaprozin, 612 oxaxilidinones, 642, 648 oxidation, 62 P450-independent mixed oxidations, 65 oxidative phosphorylation, 437 oxotremorine, 507 oxprenolol, 492 oxycodone, 573 oxymetazoline, 492 p21, 406 p38, 150, 153, 413, 639 p53, 406–7, 411–13 p75, 115 paclitaxel, 263 pactimibe, 449 pain, 12–13, 36, 38, 100, 123, 163, 260, 313, 320, 324–5, 331, 339, 461, 475, 510–511, 528, 547, 549, 562, 565, 570–571, 573–4, 578–9, 582, 584, 590–601, 612 inflammatory, 562 neuropathic, 562 palivizumab, 239, 695 palmitoylation, 137 palonosetron, 517 pancreatic cells, pharmacological stimulation of β-cell, 458–9 pancuronium, 504, 506 panitumumab, 214, 695 para-aminohippuric (PAH), 56 para-aminosalicylic acid (PAS), 642 Paracelsus, 10 paracetamol, 62, 612, 638, 682 parachlorophenylalanine, 513–14 parathion, 500 Parkinson’s disease, 480–486, 507, 560 drugs, 494, 498, 506, 507 paroxetine, 366, 515 partition coefficient, 23–6, 29, 32, 36, 38–41, 46, 56 Pasteur, L., 12 patch clamp technique, 186, 372 patent, 691–2 pazopanib, 214 PC12 cell differentiation, 169 pefloxacin, 642, 649 pemoline, 485 penciclovir, 655–6 penicillin binding protein, 645 penicillin G, 36, 41, 642 penicillins, 56, 642, 645 discovery, 14 pentamidine, 338 pentavalent antimonial, 338 pentazocine, 49, 573 peptide maturation, 386 peptidergic neurons, 568 peptidergic transmission, 568–9 perhexilline, 438 peroxisome proliferator-activated receptors (PPAR), 272, 282, 446–8 pharmacological modulation, 447 PPARα, 282, 438 PPARα agonists: fibrates, 447 PPARα/γ agonists, 283, 448 PPARα regulated genes, 282 PPARβ, 282 PPARγ, 282, 438 PPARγ agonists: thiazolidinediones, 282, 447–8, 460 PPARγ regulated genes, 282 personalized medicine, 712 pertussis toxin, 193–4 pertuzumab (Perjeta), 214 p-glycoprotein, 263, 683, 685 pH, 24 gastric, 34 pharmaceutical form, 696 pharmaceutical interactions, 685 pharmacoeconomics, pharmacogenetics, 5, 256–67 future trends, 266 pharmacogenomics, 5, 256 pharmacognosy, pharmacokinetics, 5, 694–5, 700–707 clinical, 704–5 formulations, 706 generics, 706 in vitro, 700–707 in vivo, 700–707 pharmacology arab, biotechnology, 15 clinical, egiptian, hebrew, medieval, renaissance, 10 romans, safety, 694, 696 twelve century, 15 pharmacotherapy, modern, 14–15 phencyclidine, 124, 126 phenobarbital, 4, 49, 57, 69, 70, 85, 273, 283, 680, 682 phenol-O-methyltransferase (POMT), 67 phenoxybenzamine, 486–7, 491–2 phentermine (phen), 513 727 phentolamine, 492 phenylalkylamines, 320, 328, 330 phenylbutazone, 56, 612 phenylephedrine, 492 phenyl histamine, 527 phenylpropanolamine, 485, 492 phenytoin, 51, 320, 325 phosphatidylcholine (lecithin), 499 phosphatidylinositol 3-kinase (PI3K), 155, 194 phosphodiesterases, 196 phosphodiesterase-4, 639 phospholipases, 609 phospholipase C, 196–8 phosphomycin, 642, 645 photosensitization, 670 physiologically based pharmacokinetics (PBTK)/toxicokinetics (PBPK) modeling, 673 physostigmine (eserine), 187, 499, 505 picrotoxin, 531, 534 pigmentous retinitis, 192 pilocarpine, 504, 506, 507 pimozide, 338 pinacidil, 335 pindolol, 493 pioglitazone, 282, 440, 447, 458, 460 piperacillin, 642 pirenzepine, 504, 506–7 piroxicam, 612 pituitary GH-secreting adenomas, 194 placebo, placental barrier, 29–30 plasma concentration, 39, 73–88 fluctuations, 79–80 free drug, 50–51, 82 peak, 75 protein bound, 50–51 steady state, 77–8 time course, 73–81 time-to-the-peak, 39, 74–5 plasmamembrane Ca2+ ATPase, 351–2 plasma proteins, 50–51, 81 binding to, 50, 59, 81 plasminogen, 396–9 plasminogen activator, 397–6 inhibitor, 396 platelets, 226, 228–9, 232 activation, 228–9 platinum compounds, 418 p75NTR, neurotrophin receptor, 167 poisoning, 9, 421, 500, 505–6, 584, 684 poly-(ADP-ribose)-polymerase (PARP), 549 polyamines, 653 polyenes, 654 polymixins, 525, 642, 650 polymorphisms, 182, 192, 257–66, 363, 584, 633 728 Index polypeptides, 642 posizolid, 642 post-synaptic density protein 95 (PSD-95), 473 posttranslational modifications, pharmacological modification, 130–138 potassium (K+) channels, 331–9, 456 transmembrane segments, (KATP), 332–5 composition, 332 pharmacology, 332 SUR composition, 332 transmembrane segments, 336 transmembrane segments voltage gated (VGKC), 336–9 EAG type, 336 ERG type, 336 LQT type, 338 Shaker type, 336 transmembrane segments (7TM), 339 Ca2+-activated K+ channels (BK channels), 340 potassium conductance, 557, 560, 562 potency, 100–101, 103–4, 106, 108 PP1 phosphatase, 406 pralidoxime, 500 pralnacasan, 387, 391 pramicidins, 651 prasugrel, 262, 561 pravastatin, 440 prazosin, 108, 491 precautionary principle, 676 precocious puberty, 192 prednisolone, 187, 280 prednisone, 280, 628–9 pregnane X receptor, 272–83 regulated genes, 283 pre-initiation complex (PIC), 243–6, 249–50 preladenant, 561 prenylation, 136, 163 prepropeptide, 566 Priestley, J., 11 pristinamycin, 642 probenecid, 49, 56–7, 680, 684 probucol, 338 procainamide, 57, 262, 325, 338 procaine, 36, 65, 324 procyclidine, 506–7 prodrug, 61 progesterone, 263 progesterone receptor, 272–81 antagonists, 278 progestins, 270, 280 prohormone convertases, 567 prokineticin (PK2), 569, 571 promoter, 110, 244, 272, 600, 627, 632 distal, 246 downstream element (DPE), 244 minimal, 244 proximal elements, 244–6 upstream element (UPE), 246 proopiomelanocortin (POMC), 567, 570 propafenone, 71, 325 propeptide, 566 propranolol, 58, 325, 492 prostanoid receptors, 167, 618–20 PGD2 receptors, 618 PGE2 receptors, 619 PGI2 receptors, 619 TXA2 receptors, 619–20 prostanoids, 608–614 PGD2, 609, 614 PGE2, 609, 614–15 PGF2, 609, 614 TXA2, 609, 613–14 prostanoid synthase, 613–15 prostaglandin D synthase, 614 prostaglandin E synthase, 614–15 prostaglandin F synthase, 614 prostaglandin H synthase, 610–613 prostaglandin H synthase pathway, 610 prostaglandin I synthase, 614 thromboxane synthase, 613–14 protease domain, 397 protease inhibitors, 379, 382, 392–3, 399, 655, 657, 660 proteases, 379–93, 521, 525, 567, 658, 660 proteasome, 387–8 inhibitors, 425 protein kinases, 131–2 activation, 132 5’ AMP-activated protein kinase (AMPK), 459–60 calcium/calmodulin-dependent protein kinase II, 131 protein kinase A (PKA), 131–2, 184, 196, 523 protein kinase C (PKC), 184, 197 protein phosphatases, 132–3 protein phosphorylation, 130–135 protein tyrosine phosphatases, 434 proton pump inhibitors, 3, 15, 347, 351 prucalopride, 518 P-selectin, 523 pseudoephedrine, 485, 492 pseudomonic acid, 642 p66Shc, 434 psilocybin, 124 psoriasis, 564 purinergic receptors, 553–64 P1, 556–64 P2, 556–64 P2X, 557–8, 560–564 P2Y, 557–63 purines, 553–64 pyridostigmine, 500, 505 pyridoxal-phosphate-6-azophenyl-2’,4’disulphonic-acid (PPADS), 557, 559 pyrimidines, 335, 553, 555 pyruvic dehydrogenase, 438 quantal release, 470 quantitative structure-activity relationship (QSAR), 673, 693 quetiapine, 338, 516–17 quinidine, 325, 338, 680–681 quinine, 338 quinolones, 338, 642, 649 quinpirole, 490 quinupristin-dalfopristin, 642 Rab, 156 Rac, 156 radezolid, 642 RAF, 152 raloxifene, 279, 281 R-(α)-methyl-histamine, 527 Ran, 154–7 ranitidine, 527–8 Rap, 156, 157 rapamycin, 263, 424, 627, 630, 632–3 rapsyn, 176 Ras, 154–6 Ras-dependent transduction pathway, 209–10 Ras protein, 155–6, 163 REACH regulation, 673 reboxetine, 366, 486 receptor, 5, 93, 109–20 autoreceptor, 176–7, 482, 488, 491, 501, 512, 515–16, 520, 538 cell membrane, 6, 110 complex, 94 constitutively active, 107–8 cytoplasmic duality of receptors, 166 density, 97, 108 desensitization, down regulation, 7, 117–18 endocytosis, 116 frizzled receptors, 167 heteroligomeric receptor, 177–8 homomeric receptor, 177–9 hypersensitivity, 117 intracellular, 6, 110 localization, 116–17 modulation of the activity, 109–19 nuclear, 110, 166 nuclear classes 1-3, 272 nuclear signal transduction, 110 Index orphan receptor, 191, 560 postsynaptic receptor, 175 presynaptic receptor, 175 reserve, 106 spare receptors, 106 subtypes, 99 synthesis, 117 theory, 101–5 traffic, 117 two-state receptor model, 107 upregulation, 118 receptor classes, 109–10 cytochines, 114 death (DR), 115, 408 decoy, 116, 236 dominant negative, 237 G protein coupled, 112 guanylate ciclase activity, 114 kinase activity, 113 ligand gated, 111 lipoprotein, 116 toll-like, 115 tumor necrosis factor (TNF), 115 receptor identification, 96 pharmacological profile, 96 saturability, 96 selectivity, 95–6 specificity, 96 receptor-interacting protein-1 (RIP-1), 410, 413 receptor-interacting protein-3 (RIP-3), 410, 413 receptor interactions, 93–7 hydrogen bonds, 94 hydrophobic interaction, 94 ionic bonds, 94 irreversible, 95 reversible, 95 van der Waals interactions, 94 receptor states active, 107 inactive, 107 reduction, 65 regenerative medicine, 296, 300–303 regorafenib, 214 remifentanil, 573 renin, 330, 488, 489, 491, 493, 557, 559, 660 renin-angiotensin system, 330 repaglinide, 332–3, 458 repetitive administration, 75–80 research stages, 692 research strategy, 691 reserpine, 373, 475, 514 retigabine, 320, 335, 339 retinoic acid receptor (RAR), 272–82 translocation, 282 retinoid acid receptor, 9-cis retinoic acid receptor (RXR), 272 retinoids, 282 all trans retinoic acid, 282 Rheb, 156 rheumatoid arthritis, 564 Rho, 154–6, 194 rhodopsin, 189–90, 194 Rho family GTPases, 158–62 rifabutin, 642 rifamicins, 642, 646 rifampicin, 642 rifaximin, 642, 646 riluzole, 336, 549–50 rimonabant, 590–591 risk assessment, 673 characterization, 668 risperidone, 494, 517 ritanserin, 517 ritodrine, 492 ritonavir, 263, 387, 683 rituximab, 239, 427, 635 rivastigmine, 500, 505 rizatriptan, 516 RNA-induced silencing complex (RISC), 285, 292 RNA interference, 284–5, 426 RNA polymerase II, 243 rocuronium, 504 rofecoxib, 611–13 Roger, 12 rokitamycin, 642 roselipin, 446 rosiglitazone, 282, 283, 440, 447 rosuvastatin, 440–441 roxithromycin, 642 ryanodine receptor (RYR), 143–4 S-adenosylhomocysteine (SAH), 555–6 S-adenosyl-l-homocysteine, 525 S-adenosylmetionine (SAM), 555 S-adenosynil-l-methionine, 525 salbutamol, 492 salernitan medical School, salicylates, 56, 461, 612, 681 salinosporamide A (NPI-0052), 426 salmeterol, 492 salsalate, 458, 461 Salvarsan, 13 saquinavir, 387, 393, 685 sarcoplasmic-endoplasmic reticulum Ca2+ ATPase (SERCA), 142–3, 352–3 distribution, 351 pharmacology, 353 sarin, 500 sarpogrelate, 517 satellite cell, 301 scale-up, 697 Scatchard transformation, 98 729 Scheele, K.W., 11 Schmiedeberg, O., 12 scopolamine, 42–3, 498, 504, 506–7 secretory granules, 469 secretory vesicles, 168, 380, 385, 469, 474 sedative hypnotics, 124 seizures, 562 selectin, 114, 225–227 signal transduction, 231–2 selective serotonin reuptake inhibitors (SSRI), 511, 513, 515, 518 selumetinib, 152 Semmola, G., 12 sensitization, 123, 127 serine proteases, 380 serotonin (5-hydroxytryptamine, 5-HT), 190, 509–19 cardiovascular system, 511–13 drugs, 516–18 gastrointestinal and genitourinal sistems, 513 nervous system, 509–11 release and reuptake, 514–15 synthesis, 513–14 transporter, 511, 513–15 serotonin receptors, 515–18 5-HT1, 511–13, 515–17 5-HT2, 511–13, 515–17 5-HT3, 512, 513, 515–18 5-HT4, 511, 513, 516–18 5-HT5, 512, 516 5-HT6, 512, 516–18 5-HT7, 511–12, 516–18 serotonin transporter (SERT), 369 function, 370 pharmacology, 370 sertindole, 338, 517 sertraline, 366, 515 setrons, 517 severe combined immunodeficiency (SCID), 304–5 SH2 domains, 113, 158, 206–9, 211, 230 Shild graph, 103–4 side effects, signaling cascades, 168 signal transducer and activators of transcription (STAT), 208, 212–13, 251, 636 signal transduction inside-out, 229 outside-in, 229–31 sildenafil, 597, 606 silencer, 246 simvastatin, 264, 440–441, 450 single nucleotide polymorphisms (SNP), 257 siRNA, 284–6 in clinical trials, 291 730 Index sirolimus, 263, 424, 627, 630, 632–3 SIRT1, 249 sirtuins, 249 skeletal muscle, 301, 332, 334, 340, 352, 446–7, 477, 488, 604 sleep–wake cycle, 509, 511, 513 SMAC, 411 small G proteins, 154–65 modulation, 159–64 physiological roles, 155 posttranslational modification, 157, 163 regulatory proteins, 157–9 structure, 154 subcellular localization, 157 smooth muscle contraction, 118, 156, 158, 215, 320, 327, 510, 523–4, 527, 538, 558–9, 563, 579, 602–3, 609, 614, 617–19 snake venum toxin, 476 SNARE proteins, 329, 470–471, 475, 501, 505 sodium (Na+) channels voltage gated (VGSC), 322–6 α-subunits, 322 β-subunits, 322 cellular organization, 322 classification, 323 functional properties, 322 molecular structure, 322 pharmacology, 323 sodium-glucose linked transporters (SGLTs), 453 inhibitors, 460–461 SGLT2, 458 solifenacin, 506–7 sorafenib, 152, 214–15, 426 sordarins, 653 sotalol, 320, 325, 338, 492 sparfloxacin, 338 specific flux, 27, 52 spin-off, 689 spiramycin, 338, 642 spironolactone, 280, 676 squalene synthase inhibitors, 442–3 pharmacological activity, 443 squalestatin, 440, 443 Src, 230 Src kinase, 199 stanozolol, 281 start-up, 787 statin-induced myopathy, 264 OAT1B1 polymorphisms, 264 statins, 15, 70, 137, 157, 162–3, 264, 441–3, 679, 683–4, 691 pharmacological activity, 441 STAT protein, 208, 212–13, 251, 636 stem cells, 296–9 embryonic, 298 multipotent, 299 pluripotent, 298 steroids, 633–5 receptor, 166, 167 streptogramins, 642 Streptogramin, 640, 641, 645–46 streptomycin, 642, 647 striatal interneurons, 562 substance P (SP), 525, 565, 567, 570 substances abuse, 124 subunit, 176–9 topology, 176–9 succinylcholine, 501, 504, 506 sufentanil, 573 sugammadex, 506 suicide inhibition (inactivation), 72 sulbactam, 642 sulfadiazine, 642 sulfamethoxazole, 642 sulfation, 67 sulfinpyrazone, 612 sulfonamides, 51, 642, 649 sulfonylureas, 320, 333, 455, 458–9 sulfotransferase, 514 sulpiride, 489, 490 sumatriptan, 516 sumo, proteins, 133 sumoylation, 133–4 conjugating enzymes, 133 consensus motifs, 133 SENP enzymes, 133 sunitinib, 214 superoxide anion, 433 superoxide dismutase, 63 suramin, 557, 559 survival factor inhibitors, 423 HSP90 inhibitors, 425 PI3K/akt/mTor inhibitors, 424 raf/mek/erk inhibitors, 425 Tyr-kinase inhibitors, 424 sushi regions, 538 sympathetic system, 478–9 anatomical organization, 478 cardiovascular effects, 479 noncardiovascular effects, 479 sympathomimetic drugs, 485, 490 synapse, 465–76 active zone, 140, 465, 469 chemical, 465 cleft, 465 electrical, 465 excitatory synapse, 469, 547 immunological, 116 inhibitory synapse, 469 large dense-core vesicles (LDCVs), 566–8 plasticity, 472–4 pruning, 473 small clear synaptic vesicles (SSVs), 567 tripartite, 466 vesicles, 465 synapsin, 471 synaptogenesis, 472 synaptopathies, 468 synaptotagmin, 471 T25, 675 tabun, 500 tachykinins, 565–7 tacrine, 500, 526 tacrolimus (FK-506), 71, 222, 253, 263, 338, 627, 630–633, 679–80, 682 talavancin, 642, 650 tamoxifen, 71, 248, 261, 276, 279, 281, 426, 523, 682 tamsulosin, 492 TATA-box binding protein (TBP), 243–4 taurine, 367 taxol, 413, 416 tazobactam, 642 t‐butyl‐bicycle‐phosphorothionate (TBPS), 532 tea, 562 tedisamil, 325, 338 tedizolid, 642 tegaserod, 518 teicoplanin, 642 telavancin, 642 telbivudine, 659 tele-methylhistamine, 525 tele-methylimidazole acetic acid, 525 telomeres, telomerases, 426 temozolomide, 417–18 tenoxicam, 612 terazosin, 492 terbutaline, 492 terfenadine, 263, 338, 527 terodiline, 338 terpenic derivatives, 335 testosterone, 35, 192, 263 tetanus toxin, 329, 381, 475 tetrabenazine, 373, 514 tetra-chlorodibenzo-p-dioxin (TCDD), 666 tetracyclines, 642, 647 tetrahydrocannabinol (THC), 590 tetryzoline, 492 thalidomide, 14, 627, 630 theobromine, 554, 557, 562 Theophrastus, 8, 10 theophylline, 554, 557, 561–2 therapeutic regimen, 83–7 therapeutic window, 21, 39, 54, 80, 87, 705 therapy, personalized, 17 thiazide diuretics, 56, 347 Index thiazol ethylamine, 527 thiazolidinediones, 282, 438, 447–8, 460 thiocarbamates, 652 thioformamides, 335 thioguanine, 262, 419 thioperamide, 526–7 thiopurine methyltransferase (TPMT), 262 thiopurine-S-methyltransferase (TSMT), 67 thioridazine, 338 thiorphan, 386–7 threshold of toxicological concern (TTC), 675 thrombin, 190–193, 195 thrombosis, 561 thromboxanes, 263, 605, 618 thyroid adenomas, 192, 194 thyroid hormones, 281 receptors, 272–81 triiodothyronine, 281 thyroid-stimulating hormone (TSH) receptor, 190–195 thyrotropin-releasing hormone (TRH), 190, 194, 481, 501, 567 ticagrelor, 560–561 ticarcillin, 642 ticlopidine, 71, 560–561, 682 tight junctions see junctions timolol, 71, 325, 492 tiotidine, 526–8 tiotropium, 506 tirofiban (Aggrastat), 233 tissue plasminogen activator (tPA), 395–7 TNFR1‐associated death domain (TRADD), 410 TNF‐related apoptosis‐inducing ligand (TRAIL), 410, 413 tobramycin, 642, 647 tocainide, 320, 325–6 tocilizumab, 628, 636 tolazoline, 492 tolbutamide, 71, 259, 332, 679, 681–2 tolerance, 7, 122–3, 125, 127, 572, 580–583 adrenergic receptors, 493 antibodies, 635 GABA receptors, 534–5 glucose, 455, 560 immunodrugs, 630 metabolism, 101 nitrates, 606 opioids, 572, 580–582 toll-like receptors (TLR), 1–5, 115 tolmetin, 612 tolterodine, 506–7 topotecan, 421–2 torcetrapib, 449–50, 711 toxic agents, 672–4 annual production, 673 mechanism of action, 672 mixtures, 674 toxicity dose response, 666 evaluation new chemicals, 669 existing chemicals, 669 exposure assessment, 667 genotoxicity, 670 irritation, 670 phototoxicity, 670 reproduction, 671 sensitization, 670 test guidelines, 672 toxicokinetics, 671 toxicology, 5, 665–77, 697–8 environment, 674 risk/benefit ratio, therapeutic index, tramadol, 260, 573 tramazoline, 492 transcription regulation, 243 regulators, 275 synthetic modulators of transcription activation, 254 transcriptional control genes involved in lipid metabolism, 446 transcription repressors, 244, 246, 276 transferrin, 26 translocator protein (TSPO), 535 transmission extra-synaptic, 568 volume transmission, 468 wiring transmission, 468 transplantation, 299 allogeneic, 299 autologous, 299 transporters ATP-dependent, 345–6 ATP-independent, 346 endocytosis, 361 for excitatory amino acids, 361 traffic, 361 trastuzumab (Herceptin), 214, 417, 427–8, 695 triamcinolone, 280 tricyclic antidepressants, 366, 370, 511, 515 trifluoromethylhistamine (α-), 525 triglyceride biosynthesis, 440, 444–5 trimetaphan, 504, 506 trimethoprim, 642, 649 trimethoprim/sulfamethoxazole, 338 tripelennamine, 527 triprolidine, 527 triptans, 516 731 Trk neurotrophin receptors, 167 troglitazone, 440, 447 tropisetron, 517 tryptophan hydroxylase, 513 TSC2, 170 tubocurarine, 14, 49, 411, 502, 504, 506–7 tumor necrosis factor (TNF), 408, 410, 411, 413 TNFα antagonist, 636 TNF receptor (TNFR), 115, 410, 411 tyramine, 65, 486, 680 tyrosine kinase, 207–15 cytoplasmic, 211–12 inhibitors, 213–15 non-receptor, 211 receptors, 207 signal transducers, 208, 210 tyrosine phosphatases, 212 tyrphostin, 164 ubiquitination, 134 conjugating enzymes, 134 urapidil, 492 uric acid, 57 uridine, 556 uridine diphosphate (UDP), 553–64 galactose, 553–64 glucose, 553–64 uridine-5’-triphosphate (UTP), 553–64 urokinase (u-PA), 395–9 pro-uPA, 398 receptor (u-PAR), 399 ustekinumab, 628, 636, 695 vagusstoff, 496 valdecoxib, 611–13 valproic acid, 49, 57, 325, 530, 682 vancomycin, 642–3, 645 vandetanib, 214 varenicline, 128–9, 504, 507 vascular adhesion molecules (VCAM 1), 226, 228 vasoactive intestinal peptide (VIP), 569, 570 vasopressin, 158, 190, 482, 523, 569 vasopressin receptor, 190, 192 Vauquelin, L.-N., 12 vecuronium, 506 vedolizumab, 628, 636 vemurafenib (PLX4032), 152, 417, 425 verapamil, 263, 325, 682 vernakalant, 336–7 vesamicol, 373–4, 475, 500 vesicular transporters, 361, 372–4 acethylcholine (VAChT), 374 GABA (VGAT), 374 glycine, 374 monoamines (VMAT), 373 732 Index vidarabine, 656 viloxazine, 366 vinblastine, 263, 413, 420 vincristine, 263, 413, 420, 474 viral proteases, 392 viramidine, 658 Virchow, R., 12 vitamin A, 282 vitamin B6 (pyridoxal phosphate), 524 vitamin D, 281–2 cholecalciferol, 281 ergocalciferol, 281 vitamin D receptors, 272–82 polymorphism, 281 vitronectin, 228 volociximab (M 200), 233 volume neurotransmission (VNT), 568 von Bezold-Jarisch reflex, 512 Von Linné, C., 11 xenobiotics, 61–2, 65, 71, 258, 263, 273, 283, 682–3 activated receptors, 26 xylometazoline, 492 yohimbine, 492 warfarin, 51, 71, 84, 260, 266, 679–82, 685, 705 whole body autoradiography, 703 withdrawal, 123, 125, 127, 574, 582 Wnt receptor agonists, 167, 170 xanomeline, 504, 506 xanthines, 557, 597 xantumol, 446 zanamivir, 657 zatebradine, 321, 341 ziconotide, 320, 331 zidovudine, 655 ziv-aflibercept (Zaltrap), 214 zolmitriptan, 516 zotasetron, 516–17 zygote, 296 WILEY END USER LICENSE AGREEMENT Go to www.wiley.com/go/eula to access Wiley’s 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Brain type II SCN2A 2q23 24 CNS Brain type I SCN1A 2q23 24 CNS, PNS Old names Genes Chromosome Tissue Nav1 .2 Nav1.1 Isoforms Table 27 .3 Classification and pharmacology of VGSC 324 ION CHANNELS... type 1q25–1q 32 Cav2.3a, Cav2.3b Ni2+ (27 μM); Ni2+ (25 0 μM); SNX‐4 82 kurtoxin; (tarantula toxin) mibefradil, ethosuximide (α1E) CACNA1E Neurons (synaptic terminals, dendrites, cell body) Cav2.3... 17 17 2 CACNA1C SCNA4B SCN5A SCN5A SCN5A KCNQ1 KCNH2 KCNJ2 CACNA1C HCN4 KCNA1 CACNA1A CACNA1A CACNA1A SCN1A PDK1 PDK2/TRPP2 CaCNA1S Andersen–Tawil syndrome KCNH2 SCN5A KCNE1 KCNE2 KCNJ2 KCNQ1