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Contributors A L L E N BARNETT S A M P BATTISTA CLYDE M BURNETT E S A M Z D A J A N I E GlLLIARD JEROME M GLASSMAN PETER HEBBORN P R HEDWALL R KADATZ MARIAN M A Y JACK N MOSS K M U L L E N CHARLES J PAGET R STEGER ROBERT L STONE V C S W A M Y ROBERT I TABER ROBERT A TURNER H J WILKENS Screening Methods in Pharmacology Edited by ROBERT A TURNER Turner Associates Greenwich, Connecticut PETER HEBBORN Department of Biochemical Pharmacology School of Pharmacy State University of New York at Buffalo B.
Contributors ALLEN BARNETT MARIAN MAY SAM P JACK N BATTISTA CLYDE M ESAM Z E BURNETT DAJANI R GLASSMAN R R KADATZ STEGER ROBERT L V PETER HEBBORN P MULLEN CHARLES J PAGET GlLLIARD JEROME M K MOSS C SWAMY ROBERT I TABER HEDWALL ROBERT A H STONE J WILKENS TURNER Screening Methods in Pharmacology Edited by ROBERT A TURNER Turner Associates Greenwich, Connecticut PETER HEBBORN Department of Biochemical Pharmacology School of Pharmacy State University of New York at Buffalo Buffalo, New York VOLUME II 1971 ACADEMIC PRESS · New York and London COPYRIGHT © 1971, BY ACADEMIC PRESS, I N C ALL RIGHTS RESERVED NO PART OF THIS BOOK MAY BE REPRODUCED IN ANY FORM, BY PHOTOSTAT, MICROFILM, RETRIEVAL SYSTEM, OR ANY OTHER MEANS, WITHOUT WRITTEN PERMISSION FROM THE PUBLISHERS ACADEMIC PRESS, INC I l l Fifth Avenue, New York, New York 10003 United Kingdom Edition published by ACADEMIC PRESS, INC (LONDON) LTD Berkeley Square House, London W1X 6BA LIBRARY OF CONGRESS CATALOG CARD N U M B E R : 64-24674 PRINTED IN THE UNITED STATES OF AMERICA List of Contributors Numbers in parentheses indicate the pages on which the authors' contributions begin (209) Department of Pharmacology, Schering Corporation, Bloomfield, New Jersey ALLEN BARNETT SAM P BATTISTA (167), Life Sciences Division, Arthur D Little, Incorporated, Cambridge, Massachusetts M BURNETT (203), Revlon Research Center, Incorporated, Bronx, New York ESAM Z DAJANI (121), Department of Pharmacology, Rohm and Haas Research Laboratories, Spring House, Pennsylvania CLYDE E (249), Biological Laboratories of the Pharmaceutical Department of CIBA, Ltd., Basel, Switzerland GILLIARD M GLASSMAN (227), Director, Clinical Research and Pharmacology, Denver Chemical Manufacturing Company, Stamford, Connecticut JEROME (75, 105), Department of Biochemical Pharmacology, School of Pharmacy, State University of New York at Buffalo, Buffalo, New York PETER HEBBORN P R HEDWALL (249), Biological Laboratories of the Pharmaceutical Department of CIBA, Ltd., Basel, Switzerland R (41), The Pharmacological Laboratories of the Dr Karl Thomae GmbH, Biberach an der Riss, Germany KADATZ IX LIST OF CONTRIBUTORS X (85, 101), Center for Theoretical Biology, State University of New York at Buffalo, Buffalo, New York MARIAN MAY JACK K N MOSS (121), Department of Pharmacology, Rohm and Haas Research Laboratories, Spring House, Pennsylvania (249), Biological Laboratories of the Pharmaceutical Department of CIBA, Ltd., Basel, Switzerland MULLEN J Indiana CHARLES R PAGET (145), Lilly Research Laboratories, Indianapolis, (61), Department of Biochemical Pharmacology, School of Pharmacy, State University of New York at Buffalo, Buffalo, New York STEGER L Indiana ROBERT STONE (145), Lilly Research Laboratories, Indianapolis, V C SWAMY (1), Department of Biochemical Pharmacology, School of Pharmacy, State University of New York at Buffalo, Buffalo, New York I TABER (209), Department of Pharmacology, Schering Corporation, Bloomfield, New Jersey ROBERT ROBERT A TURNER ( 21 ), Turner Associates, Greenwich, Connecticut H J WILKENS (61), Department of Biochemical Pharmacology, School of Pharmacy, State University of New York at Buffalo, Buffalo, New York Preface The second volume of "Screening Methods in Pharmacology" has the same basic purpose as Volume I, namely, to present sufficient practical information about techniques so that it would be possible for the reader, even with little experience, to establish a screening program for a particular pharmacological activity The contributors to this volume have presented typical results obtained for selected reference compounds, which are intended to show the responses with a known substance and to guide the reader during the initial use of a test method so that he may select suitable doses of the reference drugs and may know the intensity of the response expected for a certain dose level Because the progress in developing methods has been so rapid since the appearance of the previous volume, it became impossible for one person to review the pharmacological literature Thus, unlike Volume I, Volume II is a multiauthored, coedited work ROBERT A TURNER PETER HEBBORN xi Contents of Volume I Introduction A Brief Review of the Biochemistry of the Nervous System The Organization of Screening General Methods Quantal Responses Calculation of the ED Depressants of the Central Nervous System Ataractic ( Tranquillizing, Neuroleptic) Agents Analgesics Oxytocic Agents Antiserotonin Agents Parasympatholytic Agents Sympatholytic Agents Anti-inflammatory Agents Anticonvulsants Sympathomimetic Agents Central Stimulants Muscarinic Agents Ganglion-Blocking Agents Antifibrillatory Agents Cardiotonic Agents Histamine-like Agents Antihistamine Agents Antitussive Agents Antacid Agents Thyromimetic Agents Hypoglycémie Agents Choleretic Agents Antiparkinson Agents Anti-inflammatory and Glucocorticoidal Agents Antiemetic Agents Bronchodilatant Agents Curariform Agents Anabolic, Androgenic, and Antiandrogenic Agents Potentiators and Antagonists of Tryptamine Vasopressive Peptides Diuretic and Natriuretic Agents Anticholinesterase Agents Anticholesterol Agents Uricosuric Agents Antishock Agents Hemostatic Agents Local and Spinal Anesthetics Abortifacient Agents Thymoleptic Agents Dermal Irritants Teratogenic Agents Appendix References Author Index-Subject Index Introduction Numerous methods often exist for screening a series of compounds for a given pharmacological activity Many, but not all, available methods are described in this volume They have been selected because they are the most reliable, the simplest, and, in the opinion of the respective authors, the preferred of the available methods The sensitivity of the assay procedure and the possibility of ranking the compounds that have proved clinical effectiveness are important factors in the selection of a screening method Those who have been involved with screening drugs for pharmacological activity for even a short time have realized that only a few in a group of substances have activity An alternative situation exists if one has a group of compounds, all of which have varying degrees of activity In both cases, the screening process is an attempt to identify, by one or more tests, those few substances which are gems among a group of pebbles Generally it is better to use a screening method which may give a few false positives rather than one which will yield some false negatives If a substance has no true activity and is shown by a test to have activity, a false positive results Sooner or later, as testing with the substance is continued, its inactivity will be revealed Some time may be wasted in studying the compound, but in the end the investigator is not misled On the other hand, a false negative may result in the removal of a substance from further study, so that its activity will remain forever undetected The developer of a new drug is always seeking a relation between xv XVI INTRODUCTION chemical structure and biological activity, which, if found, is rare and retrospective, rather than deductive Sometimes structural changes in a molecule that appear minor cause unpredictable and extensive changes in the pharmacological activity, including loss of all activity and introduction of new side effects Often the first member of a homologous series of compounds is the most active pharmacologically Because the biological consequences of small changes in chemical structure are not understood, the structural changes cannot be programmed logically New drugs of a unique character will probably be derived in the future from novel structures rather than from modifications of old structures, study of enzyme systems involved in the disease state, unexpected clinical observations, and an understanding of the metabolism of known, active drugs Experience and scientific intuition play their important roles Screening efficiently for certain pharmacological activities is necessary for progress Since activity is unpredictable, the number of activities covered by the screening program should be considerable If several tests have indicated that a compound has some activity, it is usually advantageous to study it further rather than to start with a new compound ab initio Contemporary investigators of new drugs tend to screen with a broad program No procedure for screening can be perfect Therefore, anyone performing screening in pharmacology should always be vigilant for borderline results and for results indicating an inactive substance when one strongly suspects that activity is present If one has good theoretical grounds for anticipating activity of a substance, one should continue to study it, even if one screening procedure indicates that activity of a certain kind is absent One should not rigidly accept the results of screening procedures, if, by doing so, one would relegate to the shelf a substance which might be valuable clinically It is possible for a drug to be metabolized or eliminated very rapidly by laboratory animals and yet to have a prolonged half-life in man Phenylbutazone is an example of a drug having antirheumatic activity in man, but whose activity as an antiinflammatory agent in rodents is demonstrable only at doses approaching a lethal level Moreover, in some disease states, available, clinically effective drugs are only palliative and not curative It is reasonable to conclude that pharmacological screening tests in which such clinically active drugs have a positive effect can be used to select new drugs which are also palliative and not curative One should, therefore, be continually searching for new screening methods based on animal models of human disease processes Elucidation of the etiology of clinical disease states still requires ex- INTRODUCTION XV11 tensive effort When an abnormality in cellular function can be identified as the consequence of a biochemical lesion, then the primary screening method for new drugs will involve a biochemical assay procedure In the meantime, the pharmacological screening methods of the types described in this volume will be needed for the discovery of new drugs Finally, there are no screening methods that not require the exercise of judgment and discretion on the part of the researcher ROBERT A TURNER PETER HEBBORN 274 AUTHOR INDEX Mitsui, A., 155, 164 Miyaké, T., 104, 107, 108, 110, 119 Montagna, W., 80, 83 Moran, J F., 2, 19 Moran, N C , 37, 38, 40 Morawitz, P., 46, 60 Morpurgo, C , 211, 215, 225, 226 Morrison, B., 17, 19 Morton, L P., 124, 140 Moses, C , 123, 142 Mosettig, E., 229, 247 Mouri, T., 63, 72 Mouton, D., 155, 163 Müller, O F., 44, 60 Müller-Eberhard, H J., 163, 164 Mujic, M., 14, 19 Muller, J C , 210, 225 Munson, A E., 62, 63, 72 Murakawa, S., 53, 59 Mustard, J R., 135, 142 N Nakamara, F., 131, 132, 142 Nakamura, K., 53, 59 Nakatani, H., 129, 131, 132, 133, 134, 136, 141 Nallar, R., 113, 119 Naquet, R., 212, 225 Nash, C W., 9, 19 Nathan, H C , 151, 152, 153, 164 Neill, J M., 51, 60 Nelson, N A., 128, 142 Nettesheim, P., 146, 164 Newbould, B B., 147, 164 Nichols, J R., 244, 247 Nickerson, M., 2, 19, 24, 40 Nies, A S., 63, 73 Nikerson, R J., 127, 142 Nixon, C W., 172, 202 Nordenfeit, L, 34, 40 Nordin, A A., 152, 155, 164 Northover, B T., 19 O Oblath, R W., 54, 59 O'Bleness, G V., 13, 18 Ochs, H., 163, 165 Ogawa, Y., 107, 110, 119 Ohlin, P., 34, 40 Olsen, R T., 134, 142 O'Mant, D M., 147, 164 Orahovats, P D., 232, 238, 247, 248 Orgain, E S., 210, 225 Orsini, M W., 115, 119 Osawa, K., 53, 59 Osborne, M., 212, 218, 225 Osher, J V., 11, 18 Ostfeld, A M., 63, 73 Oswald, S., 46, 60 Ott, W H., 128, 129, 130, 134, 142, 143 Owens, M L., 211, 226 Ozaki, H., 131, 132, 142 P Padnos, M., 157, 164 Paget, C J., 147, 151, 164 Palazzo, G., 136, 142 Paoletti, P., 136, 137, 141 Paoletti, R., 136, 137, 138, 141, 142 Parikh, H M., 8, 10, 19 Park, H , 124, 142 Parkinson, M T., 128, 142 Parmenter, K., 39, 40 Parratt, J R., 46, 59 Parsons, F M., 80, 83 Parsons, W B., 123, 126, 127, 142 Partyka, R A., 129, 130, 140 Paterson, P Y., 161, 162, 165 Patil, P N., 7, 19, 32, 40 Paton, W D M., 17, 19 Patthy, A., 136, 137, 142 Paul, O., 124, 142 Pearce, J D., 162, 164 Pellmont, B., 229, 246 Penaloza-Rojas, J H., 212, 225 Perkins, E H., 146, 164 Perry, W F., 169, 202 Pescor, F T., 244, 247 Petering, H G., 152, 164 Peters, L E., 112, 119 Peterson, M J., 127, 142 Pfeiffer, F R., 131, 140 Philpot, F G., 107, 110, 119 Philpot, J ST L., 107, 110, 119 Piala, J J., 211, 212, 217, 225 275 AUTHOR INDEX Pick, R., 134, 136,142 Pickering, R W., 212, 224, 225 Pifarré, R., 53, 55, 56, 57, 60 Pilkington, T R E., 38, 40 Pincus, G., 107, 108, 110, 119 Pias, R., 212, '225 Plotnikoff, N., 213, 225 Plummer, A J., 262, 265 Porcellati, G., 138, 141, 142 Porter, C C., 211, 222, 225, 226 Potts, F A., 202 Potts, G O., 82, 83 Powell, C E , 24, 30, 40 Pritschard, W H., 44, 59 Prochard, R W., 134, 142 Pryor, W W., 210, 225 Putnam, C W., 146, 165 Q Quetsch, R M., 210, 225 Quinton, R M., 215, 225 R Rand, M J., 18 Randall, L O., 223, 225, 233, 247 Ranney, R E., 131, 142 Ratnoff, A D., 63, 72 Rayford, C R., 44, 46, 59, 60 Rees, J R., 56, 60 Reiffenstein, R J., 7, 19 Reinhard, J F., 188, 202 Reinke, D., 213, 225 Reiser, R., 135, 142 Relier, H H., 207, 208 Renyi, A L., 211, 221, 225 Revotskie, N., 123, 141 Richards, V., 28, 40 Riha, I , 154, 165 Rinzler, S H., 54, 60, 126, 140 Rittenberg, D., 127, 140 Robard, S., 46, 60, 134, 136, 142 Robinson, B F., 38, 40 Rocha e Silva, M., 61, 62, 63, 73 Rockhold, W T., 13, 18 Rodgers, D W., 233, 246 Romero, A G., 124, 143 Rosen, F S., 63, 72 Rosenberg, M Y., 53, 59 Rosenfeld, G., 61, 62, 73 Rosenman, H., 125, 141 Rosenthal, S R., 63, 73 Ross, S B., 211, 221, 225 Roswell, H C., 135, 142 Roth, F E., 10, 11, 19, 211, 224 Rothlin, E., 12, 19 Rubin, B., 214, 225 Rubio-Chevannier, H F., 212, 225 Rudel, H W., 106, 119 Ruegamen, W R., 132, 142 Russek, H L, 125, 142 Rutstein, D D., 127, 142 Rylander, R., 171, 202 S Sabiston, D C., 51, 60 Sager, R V., 125, 141 Sallata, P., 132, 133, 142 Salmonsen, C J., 146, 165 Salvador, R A., 38, 40 Sanyal, A K., 172, 202 Sarett, H P., 131, 141 Saunders, F J., 76, 83, 109, 117, 118, 119 Saunders, J T., 202 Sawyer, C H., 112, 119 Schachter, M., 61, 62, 72, 73 Schaefer, W., 233, 247 Schaper, W , 48, 52, 55, 56, 57, 60 Schild, H O., 2, 3, 5, 19 Schildkraut, J., 210, 225 Schlesinger, M J., 57, 60 Schmidt, H D., 56, 57, 60 Schmier, J., 56, 57, 60 Schneider, F., 163, 165 Schneiderman, A., 53, 59 Schnider, O., 229, 246 Schroeder, M A., 131, 143 Schuster, C R., 228, 244, 247 Schwartz, H J., 160, 165 Schwartz, R., 146, 150, 165 Scild, H O., 28, 33, 40 Scoh, A J., 147, 164 Scudi, J V., 188, 202 Seegmiller, J E., 63, 72 Seeman, T., 56, 60 276 Seevers, M H., 229, 239, 241, 242, 244, 246, 247, 248 Sefranka, J A., 131, 140 Seifter, J., 229, 246, 247 Seigal, H., 128, 134, 142, 143 Seki, T., 63, 72 Selitto, J J., 233, 247 Sever, J L., 152, 165 Shanks, R G., 23, 26, 27, 28, 30, 40 Shapiro, S., 125, 141 Sharkov, L., 132, 140 Shaw, C , 162, 165 Shemano, L, 242, 243, 247 Shipley, E G., 81, 83, 103, 104 Shipley, G C , 113, 114, 115, 118, 119 Shipley, R E., 16, 19, 44, 59, 60 Siggs, E B , 212, 218, 225 Simpson, C F., 134, 142 Sinha, P S., 172, 202 Sjoerdsma, A., 212, 222, 223, 225 Slater, I H., 24, 30, 40 Small, L F., 229, 247 Smallman, E., 152, 164 Smith, B D., 114, 119 Smith, D L., 231, 246 Smith, R F., 172, 202 Smith, W G., 15, 19 Sorrels, M F., 135, 142 Soûles, K H., 152, 165 Southworth, J., 135, 142 Spencer, P S J., 213, 225 Sprancmanis, V., 129, 130, 140 Spriggs, T L B., 8, 19 Spritz, N., 129, 142 Srivastava, R K., 172, 202 Stacey, G J., 147, 164 Stack, J., 150, 165 Stahelin, H., 147, 155, 164 Stamler, J., 125, 134, 136, 142 Stanton, E J., 239, 246 Stanton, H C., 39, 40 Stare, J F., 131, 132, 141 Starzl, T E., 146, 165 Staub, M., 212, 220, 224 Stavitsky, A B., 151, 165 Stavorski, J M., 211, 222, 226 Steger, R., 62, 63, 72, 73 Stein, L., 215, 216, 226 Steinberg, D., 122, 126, 128, 129, 130, 138, 139, 142 AUTHOR INDEX Steiner, A., 135, 142 Steinman, M., 127, 140 Stephenson, W F., 238, 246 Sternby, N H., 135, 142 Sterzl, J., 150, 154, 165 Stevenson, J W., 135, 140 Stewart, J W., 61, 72 Stewart, P B., 157, 165 Stiffel, C., 155, 163 Stjernswärd, J., 146, 165 Stohlman, F., Jr., 161, 164 Stokes, J., 123, 141 Stone, C A., 12, 19, 211, 212, 214, 215, 218, 219, 220, 222, 226 Stone, R L., 147, 151, 164 Stormby, N G., 134, 142 Strani, G., 136, 142 Stresemann, E., 63, 72 Stromblad, B C R., 34, 40 Stucki, J C., 115, 116, 117, 119 Suchowsky, G K., 116, 119 Sulser, F., 211, 213, 215, 226 Sulverman, F R., 132, 142 Sutter, M C., 10, 11, 19 Suzuki, S., 155, 164 Swyryd, E A., 129, 140 Symchowicz, S., 212, 219, 220, 224 Szolcsanyi, J., 3, 8, 9, 10, 11, 18 T Taber, R I., 211, 212, 213, 219, 220, 224 Takenaka, F., 19 Takesue, E L, 233, 247 Taleisnik, S., 114, 119 Tamasi, G., 136, 137, 142 Tatum, A L., 241, 247 Tavat, S., 236, 247 Tavella, M., 136, 142 Taylor, C B., 135, 140, 142 Telford, J., 230, 246 Tenen, S S., 216, 226 Tennent, D M., 128, 129, 130, 134, 142, 143 Tepper, S A., 132, 133, 134, 142 Terasaki, P L, 146, 165 Terenius, L., 96, 100 Theobald, W., 215, 225 Thomas, A P., 172, 202 277 AUTHOR INDEX Thomas, H E., 126, 130 Tilden, J H., 16, 19 Timms, A R., 128, 138, 143 Titterington, E., 38, 40 Titus, E T., 210, 225 Toja, E., 138, 142 Toki, K, 132, 133, 141 Tomiyasu, U., 124, 140 Totaro, J A., 211, 222, 225, 226 Tozzi, S., 30, 40 Trapold, J H., 129, 138, 143 Travell, J., 54, 60 Tremer, H M., 172, 173, 202 Trendelenburg, U., 4, 17; 19 Triggle, D J., 2, 19 Tsuchiya, M., 190, 202 Turk, C F., 147, 162, 164 Turk, J L., 160, 161, 165 Turner, R A., 255, 265 Tye, A., 7, 19 Tyson, F T., 229, 246 U Umar, M S., 10, 19 Unna, K., 229, 247 Ursillo, R D., 212, 219, 226 Usama, B S., 157, 163 V Valzelli, J., 211, 226 Van Beaumont, W., 204, 208 van den Brink, F G., 5, 19 Van Rallie, T B., 128, 141 van Rossum, J M., 5, 6, 7, 8, 14, 19 Van Slyke, D D., 51, 60 Varma, D R., 39, 54, 60 Velardo, J T , 111, 119 Veneroni, E., 131, 140 Verity, M A., 18 Vernier, V G., 214, 215, 226 Villarreal, J E., 228, 244, 247 Vineberg, A M., 53, 55, 56, 57, 60 Vohra, M., 7, 19 von Euler, U S., 222, 226 W Wagner, H R., 51, 60 Wald, A., 250, 265 Waldeck, B., 211, 221, 222, 225, 226 Walkenstein, S., 229, 246 Walker, J D., 77, 83 Wang, G H., 204, 208 Ward, J W., 232, 233, 247 Warner, B., 212, 224, 225 Watanabe, N., 63, 72 Watzman, N., 233, 247 Waugh, M., 214, 225 Wearn, J T., 44, 59 Weatherby, J H., 172, 202 Webster, M E., 63, 72 Weikel, J H., 26, 33, 40 Weinstein, W., 43, 60 Weiss, B., 234, 247 Weissman, A., 215, 216, 226 Weitzel, G., 163, 165 Wemblatt, E., 125, 141 Wendel, H., 242, 243, 247 Werle, E., 62, 69, 72, 73 Werner, G., 53, 60 Werthessen, N T., 107, 108, 119 West, J W., 44, 53, 60 Whitby, L G., 210, 224 Whitehouse, M W., 147, 164 Whiteside, C H., 131, 141 Whittle, B A, 213, 226 Wiegand, R G., 216, 225 Wigand, G., 134, 135, 142, 143 Wiggers, C J., 53, 60 Wikler, A., 244, 247 Wilcoxon, F., 214, 218, 224, 225 Wilkens, H., 63, 73 Williams, F., 46, 60 Williams, H E., 63, 73 Williams, M C., 135, 142 Wilson, C., 44, 60 Wilson, J D., 76, 77, 83 Wilson, R E., 158, 163 Winbury, M., 42, 43, 51, 52, 53, 54, 60 Winter, C A., 230, 232, 238, 247, 248 Wissler, R W., 131, 135, 136, 143, 152, 165 Wohl, A J., 10, 11, 19 Wolf, F J., 128, 134, 142, 143 Wolff, H G., 63, 73, 231, 248 Woodbury, L., 80, 83 278 AUTHOR INDEX Woodruff, M F A., 147, 165 Wortis, H H., 154, 164 X Xhonneux, R., 48, 52, 55, 60 Y Yamamoto, S K., 138, 141 Yanagita, T., 244, 248 Yochim, I M., 95, 100 Yonkman, F F., 238, 248 Yoshinaga, K., 63, 72 Young, W., 124, 143 Yudkin, J., 124, 143 z Zahn, A., 46, 60 Zanetti, M E., 128, 129, 130, 134, 142, 143 Zarrow, M X., 112, 119 Zauder, H L., 238, 248 Zeller, J H., 135, 140 Zins, G R., 255, 265 Zuberbuhler, R L., 10, 19 Subject Index A Abstinence syndrome, 228, 229, 239, 241 Abuse potential agents, antidiuresis and, 236 mania in cats, 236 physical dependence, 239-243 psychic craving, 243-244 screening methods for, 235-244 tolerance, 235 Aceperone, Acetazolamide, 258, 259 Acetylcholine, 67 3-Acetyl-5- ( 4-fluorobenzylidene ) -4hydroxy-2-oxo-2,5-dihydrothiophen, see Compound 47,776 Acetylsalicyclic acid, 232 Actinomycin C, 153 Actinomycin D, 153 Adamantoyl cytarabine, see Cytosine arabinosides Adenosine diphosphate, 67 Adenosine triphosphate, 67 Adenyl cyclase, 37 ADP, see Adenosine diphosphate, «-Adrenergic blocking agents, see also specific drugs pA values of, 8, 10 screening methods for, - intact animals, 15-18 isolated organs, 4-15 /3-Adrenergic blocking agents, see also specific drugs antifibrillatory effects, 39 antilipolytic action of, 37 metabolic effects of, 37-39 nomenclature, 24 screening methods for, 26-35 therapeutic uses, 39 Adrenergic receptors, blockade in intestine, 14 blockade in nictitating membrane, 17 blockade in seminal vesicles, 8, 12-13 blockade in spleen, 8, 13 blockade in uterus, 14 blockade in vascular tissue, 9-12 blockade in vas deferens, 3, 6-8 list of, 23 Ahlquist, theory of adrenergic receptors, 22 theory, exceptions to, 22 Aldehyde dehydrogenase, 223 Allergic reactions, see Anaphylaxis Allograft, see Graft rejection N-Allylmorphine, 229, 230, 232, 233, 241, 242 Aluminum chlorhydrol, 207 Ameroid constrictor, 53 Aminophylline, 32 5-Aminouracil, 153 Amitriptyline, 212, 215, 217-220 3',5'-AMP, see 3',5'-cyclic adenosine monophosphate d-amphetamine, see methamphetamine Amphetamines, 228, see also, Methamphetamine potentiation Anabolic agents, screening methods for, 81-82 Analgesic agents, see also specific drugs antidiuresis and, 236 hyperglycemia and, 238 screening methods for, 230-234 279 280 chemical method, 233 electrical method, 233, 234 pressure method, 233 thermal methods, 231-232 tolerance to, 235 Anaphylaxis, 146, 163 Androgenic agents, see also specific drugs capon comb, effect on, 78 chick comb, effect on, 77, 82 costovertebral gland, effect on, 80, 81, 82 lachrymal gland, effect on, 80 levator ani, effect on, 79, 81 preputial gland, effect on, 80 prostate, effect on, 78, 80 screening methods for, 77-81 sebaceous gland, effect on, 76, 80 seminal vesicles, effect on, 78 Androgens, see Androgenic agents 5a-Androstan-17ß-ol-3-one, see Dihydrotestosterone Androstenedione, 76 Anesthesia, dog, 26, 29, 34 cat, 26 Angiography, 57, 58 Angiotensin, 67 Anovulation, pituitary hormones and, 101, 102, 104 pregnancy, incidence of, 104 Anovulatory agents, screening methods for, 103, 104 therapeutic implications, 102 types of agents producing, 102 Antiandrogenic agents, 82, 106 screening methods for, 82 Antianginal agents, screening methods for, 59 Antibody, 147-150 chemical suppression of, 150-152 7S and 19S, 152, 154-155 Anticholinergic agents, sweating and, 203, 205 Antidepressant agents, see also specific drugs mechanisms of action, 210 screening methods for, 210-224 Antidiuretic action, 236 method for, 236-238 Antidiuretic hormone, see Vasopressin SUBJECT INDEX Antiestrogens, MER-25, 98 physiological effects of, 98 screening methods for, 98, 99 Antifertility agents, 114 Antifibrillatory agents, 39 Antihyperlipidemic agents, biological mechanisms, 138-139 screening methods for, 129-140 birds, 134, 136 dogs, 134 normocholesterolemic animals, 129 primates, 135 rabbits, 132-134 rats, 130-132, 138 swine, 135 Antihypertensive activity, test for, 261-265 analysis of data, 263 controls in, 264 criteria for activity, 264 sequential procedure for, 264 technique, 263 Antilipolytic action, 37 Antilymphocyte serum, 147, 149, 157, 158 Antiperspirant agents, 203-208 screening methods for, 204-208 footpad of cat, 204 galvanic technique, 204 gravimetric method, 206 resistance hygrometry, 204 starch-iodide technique, 205 Aorta, adrenergic responses of, rabbit, rat, 11 Apomorphine, 243 Arthus reaction, 163 Atherosclerosis, diet in, 123, 126 etiology of, 123, 126 experimental, 53-55 hypertension in, 125 immunological causes of, 125 primates, 135-136 rabbits on semi-synthetic diet, 134 smoking in, 124 stress in, 13 therapy, 126-129 ATP, see Adenosine triphosphate 281 SUBJECT INDEX Atrium, right, of guinea pig, 27 left, of rabbit, 28 Atromide, see Clofibrate Atropine, 206 Autoimmune disease, 146, 147, 161 Average sample number, 253 8-Azaguanine, 153 Azathioprine, 146, 150, 152, 153 6-Azathymine, 153 6-Azauracil, 153 B Barbiturates, 228 BCG vaccine, 160 Benzimidazole, 153 Benzimidazole phenylurea, 147 Benzmalacene, in estrogen-induced hypercholesterolemia, 136 in fat-induced hypercholesterolemia, 132 Benzo-2,l,3-oxadiazoles, 147 Benzoylscopolamine, 206 N-benzyl-N-methyl-2-propynylamine, 223 Biphenyl-a-butyric acid, 131 Blastic transformation, 161-162 Blood pressure responses, 15-17 cats and dogs, 15 rats, 16 Bradykinin, see also Kinins pain response to, 233, 234 Bretylium, 24 5-Bromodeoxyuridine, 146 9a-Bromo-ll-keto-progesterone, 117 5-Bromouracil, 153 Bubble flowmeter, 44 Butoxamine, 35 C Capon comb, 78 Carbonic anhydrase, activity in uterine endometrium, 110 progesterone and, 110 Cardiac output, 47 Carrageenin, 160 Castration, rat, technique, 78 Catecholamines, actions on a- and ^-receptors, 1, 23 factors modifying, chronotropic response to, 26 pressor responses to, 15-17 tissue sensitivity to, 6, 13 Chick comb, 77, 82 Chlorambucil, 153 Chloramphenicol, 153 Chlormadinone, 118 6-Chloro-6-dehydro-17acetoxyprogesterone, see Chlormadinone Chloroprophenpyridamine, 189 Chlorphensin, 160 Chlorpromazine, 8, 213 Chlorthalidone, 259 Cholestyramine, hyperlipidemia therapy, 127 hypocholesterolemic effect in weanling rats, 138 Chronotropic response, 22 Cilia, activity of, see also Mucociliary activity effect of ions on, 169 effect of p H on, 169 visualization of, 171 Cinanserin, 147, 162 Clam gill cilia, 182-188 Clofibrate, cholesterol biosynthesis inhibition, in vivo, 138 and hypercholesterolemia in rabbit, 133 and hyperlipidemia therapy, 128 in normocholesterolemic animals, 130, 131 Clopamide, 259 Cobra venom, 163 Cocaine, 212, 228 Codeine, 230-233, 242, 243 Collateral arteries, 55 Complement, 147 chemical inhibition of, 163 detection of plaque-forming cells, 154 Compound 47,776, 147, 152 Contact sensitivity, 160-161 Control limits, 254 Copper acetate, 113 Coronary blood flow, 43 282 SUBJECT INDEX arterial inflow, 43 cannulation technique, 44 narcosis and, 43 p C and, 43 venous outflow, 44-46 Coronary blood vessels, cannulation of, 44 casts of, plastic, 57 retrograde flow in, 53, 56 retrograde pressure in, 53, 55, 56 Coronary insufficiency, 52-57 Coronary occlusion, 53-55 acute, 53-56 gradual, 53-55 Coronary resistance, measurement of, 46-47 Coronary sinus, cannulation of, 44-46 Coronary strips, isolated, 42 Corpus luteum, 114 Corssen and Allen solution, 186 Cortisone, 146, 162 Costovertebral gland, 76, 80 CPIB, see Clofibrate Crocker mouse sarcoma, 159 Cyclazocine, 234 3',5'-Cyclic adenosine monophosphate, 37, 39, 127 iV-Cyclohexyl-linoleamide, in estrogen-hypercholesterolemia, 136 Cyclophosphamide, 146, 161, 162 Cyproterone acetate, 106 Cytarabine, see Cytosine arabinosides Cytosine arabinosides, 147, 155, 158, 159 D Deciduoma formation, 111 histamine and, 111 Delayed hypersensitivity, 149, 160-161 Deoxyribonucleic acid, immimosuppressives affecting synthesis of, 163 Dependence, drug, physical, 228, 239-243 psychological, 228 Desmethylimipramine, 219 Dibenamine, 23 characterization of activity, 2, Dibozane, 16 Dichloroisoprenaline, 24, 26, 31, 33, 37, 39 Diethyldithiocarbamate, 213 Diethylstilbestrol, estrogen assays and, 98 potency of, 87 structure of, 88 Dihydroergotamine, 30, 34 Dihydrotestosterone, 76 Dimethylisopropylmethoxamine, 35 Dipyridamole, 45, 48, 50, 56 Diuretic activity, 255 Dopamine, 32 Dopa potentiation, 216 MAO inhibitors, 216 tricyclic antidepressants, 217 Droperidol, Dyspnea, 241 E Eccrine sweat gland, see Sweat gland, eccrine Electromagnetic flowmeter, 44, 46, 47 Emesis, 237 Emotion, sweating and, 204 Ephedrine, 32, 33, 189 Epinephrine, see also catecholamines Epinephrine, 23, 31, 33-35, 37, 238 Epsilon aminocaproic acid, 71 Estradiol, antagonism of, 99 duration of action, 99 luteinizing hormone and, 86, 87 pituitary inhibition by, 86, 87 structure of, 86 uterine weight and, , 93 vaginal mitosis and, 94, 95 Estriol, structure of, 88 Estrogens, see also specific drugs assay methods for, duration of action, 99 four-day uterine weight test, 93 general procedures, 89 in vitro tests, 96 in vivo tests, 91 uterine water uptake, 91 vaginal mitosis, 94 283 SUBJECT INDEX in hypercholesterolemia induction, 136 mechanism of action, 88 natural, 87, 88 ova implantation, 115 progesterone and, 86, 87, 107, 117 synthetic, 87, 88 therapeutic uses of, 89 Estrone, 88, 115 Estrus, induction of, 111 Ethacrynic acid, 255 Ethylchlorophenoxyisobutyrate, See clofibrate Ethylnorepinephrine, response to, 16 reversal, 29, 30, 35 Exercise, sweating and, 207 Expectorant activity, 167 Experimental allergic encephalomyelitis, 149, 161 F N-(Ferrocenylmethyl) piperidine, 131 Fever, sweating and, 207 Fibrinolysin, see Plasmin Flowmeters, 44 5-Fluorouracil, 153 Formic acid, 191 Free fatty acids, 35, 37 Freunde adjuvant, 160, 161 Furosemide, 259 G Graft rejection, 146, 155-157 Graft vs host reaction, 158-159 Guanethidine, 24, 265 Guinea pig, aortic strip, 10 hypogastric nerve-vas deferens, 8-9 seminal vesicles, 12-13 vas deferens, 3, 7-8 H Hageman factor, kallikrein activation by, 62 2-Halogenoethylamines, 2, 6, 7, 12, 15 Hemagglutination, 150-152 Hemodynamic measurements, 30 Heparin, in hyperlipidemia, 127 Hexamethonium, 24 Histamine, 33, 67, 111, 147, 163 Homograft, see Graft rejection Host vs graft reaction, 158 Hot-plate method, 231 Hydralazine, 265 Hydrochlorothiazide, 256, 259, 260 Hydrocortisone, 153 6-Hydroxydopamine, 222 3a-Hydroxy-5a-pregnan-20-one, 109 17a-Hydroxyprogesterone acetate, 117 5-Hydroxytryptamine, 67, 185 5-Hydroxytryptophan, potentiation of, 224 5-Hydroxyuracil, 153 Hypercholesterolemics, see Atherosclerosis Hyperglycemia, 35, 37 Hyperhidrosis, 203 Hyperlipidemia, see Atherosclerosis Hypersensitivity, see Anaphylaxis Hypothermia, 213 I Imipramine, 215, 216, 218, 220 Immunocytoadherence, 155 Immunosuppressive agents, 145-165, see also specific drugs screening methods for, 150-163 types of, 146 uses of, 145 Indoleacetic acid, 223 Inotropic response, 22 Intestine, adrenergic response of, 14, 16 Ischemia, myocardial, 53 Isoprenaline, 23, 24, 27, 31, 33, 34 D-isomer, 31 Isoprophenamine, 29, 30 N-Isopropylmethoxamine, 35 K Kallidin, 62 Kallikrein, 62, 63 Kallikrein-Kinin system, 62, 63 activation of, 62 284 acetone, 62 acidification, 62 Hageman factor, 62 PF/Dil, 62 plasmin, 62 trypsin, 62 components of, 62 aminopeptidase, 62 kallikrein, 62 kininases, 62 kininogen, 62 methods of assay for, 64-72 pre-kallikrein, 62 inhibition of, 62-63 epsilon aminocaproic acid, 71 kininases, 62 lima bean trypsin inhibitor, 63, 71 ovomucoid trypsin inhibitor, 71 proteolytic enzyme inhibitors, 63, 71, 72 soybean trypsin inhibitor, 63, 71 Trasylol, 63, 71 Ketobemidone, 236 Kininase, 70, 72 Kinin-like activity, see Kinins Kininogen, 70 denatured, 70 native, 70 Kininogenases, 66-69, 71 identification of, 71, 72 inhibitors of, , 72 kallikrein, 69 kallikrein, dog salivary, 69, 71 kallikrein, human pancreatic, 69, 71 kallikrein, human plasma, 69, 71 kallikrein, human urinary, 69, 71 kallikrein, rat plasma, 69, 71 kininogen substrate, 68 pre-kallikrein, 66-69 Kinins, 61-73 bioassay, apparatus for, 64, 65 procedure, 64-66 chemical structure of, 62 identification of, 66, 67 pathophysiological roles of, 63 pharmacological actions of, 61 physico-chemical properties of, 62 adsorption onto glass, 62 p H effect, 62 temperature effect on, 62 SUBJECT INDEX physiological roles of, 63 Krebs-Henseleit solution, 32 L Lachrymal gland, 80 Lachrymation, 241 Langendorff heart, 30, 42 Levallorphan, 240 Levator ani, 79, 81 Levopromazine, Lidoflazine, 48, 55 Lima bean trypsin inhibitor, 71 Locke's solution, 30 Luteinizing hormone, 106, 113, 114 and ovulation, 114 Lymphocytes, 147 blastic transformation of, 161-162 macromolecular synthesis in, 162-163 Lysylbradykinin, 67 M Macusine-B, 8, 10 Mania, cat, 236 Marihuana, 228 McEwan's solution, 27 Menstrual cycle, 105 anovulatory, 106 Meperidine, 229, 230, 232, 233, 235, 236, 238 Mer 29, see Triparanol 6-Mercaptopurine, 146, 152, 153 Metabolic effects, of /9-adrenergic blocking agents, 37 Metabolism, myocardial, 51-52 Methacholine chloride, 32 Methadone, 240 Methamphetamine potentiation, 211, 215, 216 anorexia, 216 excitation, 215 self-stimulation, 216 Methapyrilene, 189 Methimazole, 134 A-Methopterin, 153 Methotrexate, 146, 153, 161 Methoxamines, 35 6a-Methyl-17a-acetoxyprogesterone, see Provera 285 SUBJECT INDEX Methyl- 19-nortestosterone, 117 6-Methylthiopurine, 153 Monoamine oxidase inhibitors, 222 5-hydroxytryptophan potentiation, 224 in vitro methods, 222 in vivo methods, 223 Morphine, 229-243, see also Analgesic agents abstinence syndrome, 229, 239 antagonists, 229, 232 antidiuresis, 236 emesis, 237 hyperglycemia, 238 mania in cats, 236 physical dependence, 239-243 respiratory depression, 229 Mucociliary activity, agents affecting, medical uses of, 167 screening methods for, 171-201 in vitro methods, 171-191 in vivo methods, 191-201 Mucus, 168-171, 192 Muricide antagonism, 211, 217 Myotropic activity, see Anabolic agents N Nalorphine, see N-AUylmorphine Naphazoline, 189 Narcotic drugs, 228 antagonists, see N-Allylmorphine Pentazocine Natriuretic activity, test for, dog, 259-261 analysis of data, 260 criteria for activity, 261 sequential procedure for, 261 technique, 260 test for, rat, 254-258 analysis of data, 256 controls in, 258 sequential procedure for, 257, 258 technique, 255 test criteria, 257 Neuroleptic agents, 215 Nicotine, 191 Nicotinic acid, 127 Nictitating membrane, 17, 18, 23 relaxation of, morphine, 237 Nitrogen dioxide, 191 Nitrogen mustard, 146, 153 5-Nitrouracil, 153 Norepinephrine, 23, 34, 238 see also catecholamines Norepinephrine potentiation, 218 blood pressure, 218 innervated guinea pig vas deferens, 219 vas deferens, 219 Norepinephrine uptake, 220 cerebral cortex slices, 221 heart, 221 Norethindrone, 106 Norethynodrel, 106 A-Norprogesterone, 82 19-Norprogesterone, 113, 114 19-Nortestosterone, 82 Nucleic acid synthesis, immunosuppressive effects on, 162-163 O Operating characteristic curve, 252 Opiates, 228 Opiods, 228 Oral contraceptive agents, 89 Organ transplantation, see also Graft rejection use of immunosuppressives in, 146 Ova, implantation of, 115 Ovalicin, 147, 155 Ovariectomy, technique for, 90 Ovomucoid trypsin inhibitor, 71 Ovulation, copper acetate and, 113 facilitation of, 112 inhibition of, 89, 101, 102, 113 luteinizing hormone and, 113 pregnant mare serum gonadotropin and, 112 Ovulatory cycle, 85, 86, 87 Oximeter, 51-52 Oxygen consumption of the heart, 51 Oxygen tension, 52 microelectrodes, 52 polarographic measurement, 52 Oxytocin, 67 286 SUBJECT INDEX P pA, value, 28, 32 pAh value, 3-4 pA x value, α-adrenergic blocking agents, 8, 10 determination of, 3, 5-6 Pain, types of, 230 relief of, see Analgesic agents Papaverine, 33, 242 Papillary muscle, 30 Pargyline, 217 Parotid gland, 34 Passive cutaneous anaphylaxis, 163 Pentaerythrityl tetranitrate, 56 Pentazocine,'230, 231, 233, 234 PF/Dil, 62 1,10-Phenanthroline, 69, 70 Phenethylamine antagonism, 219 blood pressure, 219 vas deferens, 220 Phenoxybenzamine, 2, 15, 23 Phentolamine, 2, 6, 8, 10, 23 Phenylephrine, 5, 16 ß-Phenylisopropylhydrazine, 223 Physical dependence, 228, 239-243 sustaining potency, 240 Phytohemagglutinin, 161-162 Picryl chloride, 160 Pigs, use in coronary experiments, 47-49 Piperoxan, 8, 10 Pithed rats, pressor responses of, 16 Placebo, 259 Placenta, 105 Plaque-forming cells, 152-155 Plasma cells, 147 Plasmin, 62 Plastics for coronary casts, 57 PMS, see Pregnant mare serum gonadotropin Polyinosinic acid, 163 Polymorphonuclear leukocytes, 147, 163 Polypeptides, hypotensive, 61 Prednisone, 146 Pregnancy, maintenance of, 109, 115-118 Pregnant mare serum gonadotropin, 112 Preputial gland, 80 Procarbazine, 147, 157, 159 Progestational agents, see also specific drugs effect on corpus luteum, 114 effect on luteinizing hormone, 106, 113, 114 effect on ova implantation, 115 effect on ovulation, 112-114 facilitation of, 112 inhibition of, 113 effect on pregnancy, 115 effect on uterine endometrium, 106-112 carbonic anhydrase activity of, 110 deciduoma formation in, 111 glandular growth of, 107 screening methods for, 106-115 Progesterone, see also Progestational agents, 80, 105-118 physiological effects of, 105-106 5«-reductase, 109 Progestins, see Progestational agents Progestogens, see Progestational agents Promethazine, 211 Pronethalol, 24, 28, 31 Propoxyphene, 230-233, 242, 243 Propranolol, 24, 28 6-Propylthiopurine, 153 Propylthiouracil, 131, 132, 135 Prostate, 78, 80 Protein synthesis, immtmosuppressive effects on, 162-163 Prothrycin, 189 Protriptyline, 219, 222 Provera, 115, 118 Pseudopregnancy, induction of, 111 Psychedelic agents, 228, 229 Psychological dependence, 228 Psychotomimetic agents, 228, 229 Ptosis, 214, 240 Pyranisamine, 189 R Reserpine, 210 Reserpine antagonism, hypothermia reversal, 213 locomotor depression, 214 ptosis, 214 Resistance hygrometry, 204 Retractor penis, adrenergic responses of, 16 287 SUBJECT INDEX Retrograde flow, 53, 56 Retrograde pressure, 53, 55, 56 Rhinorrhea, 241 Ribonucleic acid, immunosuppressives affecting synthesis of, 163 Rotameter, 44 S Salivary gland, 34 Saluretic agents, see Natriuretic agents Scopolamine, 206 Sebaceous gland, 76, 80 Seminal vesicles, 78 adrenergic responses of, 12, 13 Sequential procedure, 250-265 analysis of data, 250-251 antihypertensive activity, 263 natriuretic activity, rat, 256 dog, 260 construction of, 252-253 antihypertensive activity, 264 natriuretic activity, rat, 257 dog, 261 control limits in, 254 statistical basis for, 250-254 test criteria for, 251 antihypertensive activity, 264 natriuretic activity, rat, 257 dog, 261 truncation of, 253, 258 use of controls in, antihypertensive activity, 264 natriuetic activity, rat, 258 dog, 261 Serotonin, see 5-Hydroxytryptamine Sitosterol, 136 Skin grafting, see Graft rejection Sodium cyanide, 191 Sodium salicylate, 242 Sodium thiocyanate, 191 Soybean trypsin inhibitor, 71 Starch-iodide technique, 205 Strabismus, 241 Stroboscopy, 171 Stroke volume, 47 Structures, of /3-adrenergic blocking agents, 25 Submaxillary gland, 33-35 Sweat gland, eccrine, 203 factors affecting activity, 207 foot pad, 204 T Tachycardia, 26 Tail-flick method, 231-232 Tapazole, see Methimazole Testosterone, 75-82 5a-reductase, 76 Tetrabenazine antagonism, 214 locomotor depression, 214 ptosis antagonism, 214 Theophylline, 37 stimulation of lipolysis by, 39 Thermocouples, heated for myocardial flow, 46 2-Thiocytosine, 153 6-Thioguanine, 153 2-Thiothymine, 153 4-Thiothymine, 153 2-Thiouracil, 153 4-Thiouracil, 153 Thonzylamine, 189 Thymoxamine, 3, 8, 10 Thyroid hormones, in clinical hyperlipidemia, 128 in estrogen-induced hypercholesterolemia, 136 in triton-induced hypercholesterolemia, 138 Thyroxine, see Thyroid hormones Tolazoline, Trachea! chain, 31 Trachéal cilia, cat, 195-200 chick, 171-182, 192-195 rabbit, 201 rat, 188-190, 200 Trachéal spiral, 33 Tranquilizing agents, abuse of, 228 Trasylol, 71 Triparanol, 136, 139 Tripelennamine, 189 Triton, 136 Trypsin, 71 Tuberculin reaction, 160 288 SUBJECT INDEX Tumor heterograft rejection, 159 Tyramine, 223 Tyramine antagonism, see phenethylamine antagonism U U-26597A, 128 Urethane, 153 Uterine strips, 30 Uterus, adrenergic receptors in, 22, 23 adrenergic responses of, 14 bleeding, 106 endometrium, 105 deciduoma formation, 111 glandular tissue, 107 mucosal tissue, 108 V Vagina, conification of, 94 Vaginal opening, estrogen assay and, 93, 94 Vaginal smear, technique for, 94, 95 Variance, 251 Vascular smooth muscle, adrenergic responses of, 9-12, 29 Vas deferens, adrenergic responses of, 6-9 Vasopressin, 53, 238 Y Yohimbine, 8, 10 ... Birmingham Szolcsanyi Birmingham Szolcsanyi Rabbit aortic strip 30 7.70 Epinephrine Dihydroergotamine Phentolamine 20 7.52 Epinephrine Yohimbine 30 6.70 Epinephrine Norepinephrine Macusine B Piperoxan... Some methods for testing antianginal agents are too involved to be used as screening methods However, reliable methods which are appropriate for use in screening for antianginal activity are included... Guinea pig aortic strip Dog carotid strip Cat aortic strip nne Norepinephrine Norepinephrine Norepinephrine Thymoxamine 7.20 Thymoxamine 13 6.99 Thymoxamine — 6.10 Birmingham Szolcsanyi Birmingham