Molecular and Quantum Pharmacology: Proceedings of the Seventh Jerusalem Symposium on Quantum Chemistry and Biochemistry Held in Jerusalem, March 31st–April 4th, 1974 PDF
Preview Molecular and Quantum Pharmacology: Proceedings of the Seventh Jerusalem Symposium on Quantum Chemistry and Biochemistry Held in Jerusalem, March 31st–April 4th, 1974
MOLECULAR AND QUANTUM PHARMACOLOGY THE JERUSALEM SYMPOSIA ON QUANTUM CHEMISTRY AND BIOCHEMISTRY Published by the Israel Academy 01 Sciences and Humanities, distributed by Academic Press (N. Y.) 18t JERUSALEM SYMPOSIUM: The Physicochemical Aspects 01 Carcinogenesis (October 1968) 2nd JERUSALEM SYMPOSIUM: Quantum Aspects 01H eterocyclic Compounds in Chemistry and Biochemistry (April 1969) 3rd JERUSALEM SYMPOSIUM: Aromaticity, Pseudo-aromaticity, Antiaromaticity (April 1970) 4th JERUSALEM SYMPOSIUM: The Purines: Theory and Experiment (April 1971) 5th JERUSALEM SYMPOSIUM: The Conlormation 01 Biological Moleeules and Polymers (April 1972) Published by the Israel Academy 01 Sciences and Humanities, distributed by D. Reidel (Dordrecht) 6th JERUSALEM SYMPOSIUM: Chemical and Biochemical Reactivity (April 1973) VOLUME 7 MOLECULAR AND QUANTUM PHARMACOLOGY PROCEEDINGS OF THE SEVENTH JERUSALEM SYMPOSIUM ON QUANTUM CHEMISTRY AND BIOCHEMISTRY HELD IN JERUSALEM, MARCH 31sT-APRIL 4TH, 1974 Edited by ERNST D. BERGMANN Department o/Organic Chemistry, The Hebrew University Jerusalem, Israel and BERNARD PULLMAN Universite de Paris, Institut de Biologie Physico-Chimique (Fondation Edmond de Rothschild) Paris, France D. REIDEL PUBLISHING COMPANY DORDRECHT-HOLLAND / BOSTON-U.S.A. Library of Congress Catalog Card Number 74--83002 ISBN-\3: 978-94-010-1760-2 e-ISBN-\3: 978-94-010-1758-9 DOI: 10 .1 007/978-94-010-1758-9 Published by D. Reidel Publishing Company, P.O. Box 17, Dordrecht, Holland Sold and distributed in the U.S.A., Canada, and Mexieo by D. Reidel Publishing Company, Ine. 306 Dartmouth Street, Boston, Mass. 02116, U.S.A. All Rights Reserved Copyright © 1974 by D. Reidel Publishing Company, Dordreeht, Holland Softcover reprint of the hardcover 1s t Edition 1974 No part of this book may be reproduced in any form, by print, photoprint, microfilm, or any other means, without written permission from the publisher TABLE OF CONTENTS PREFACE IX FELIX BERGMANN / Introductory Remarks on Pharmacological Receptors BERNARD PULLMAN / The Adventures ofa Quantum-Chemist in the Kingdom 9 of Pharmacophores w. P. PUR CE L L / Quantitative Structure-Activity Relationships. An Approach to Drug Design 37 c. R. GANELLIN / Imidazole Tautomerism of Histamine Derivatives 43 R. R. ISON / The Conformation of Histamine, 5-Hydroxytryptamine and Some Related Derivatives in Aqueous Solution 55 ROBERT KATZ, STEPHEN R. HELLER, A. E. JACOBSON, A. ROTMAN, and C. R. CREVELING / Molecular Orbital Calculations on Catecholamines; Theory and Experiment 67 G. c. K. ROBER TS / The Conformation of Catecholamines in Solution 77 ERNST D. BERGMANN, EDNA OPPENHEIMER, HANNAH WEILER FEILCHENFELD, and SASSON COHEN / Molecular Factors and Activity in Psychopharmacologically Active Compounds 95 ALAN S. HORN, OLGA KENNARD, W. D. S. MOTHERWELL, MICHAEL L. POST, and JOHN R. RODGERS / An Approach to Possible Correlations Between Ac- tivity and Conformation in Some Classes of Psychotropic Drugs 105 HENR Y G. MA UTNER / Studies of the Conformation in Solution of Molecules Related to Acetylcholine 119 H. J. R. WEINTRAUB and A. J. HOPFINGER / Solvent-Dependent Conforma- tional Studies of Acetylcholine and Some Related Molecules 131 DAVID L. BEVERIDGE, RICHARD J. RADNA, GARY W. SCHNUELLE, and MARGARET M. KELLY / Theoretical Studies of Solvent Effects on the Con- formational Stability of Cholinergic Molecules 153 G. LAMBRECHT and E. MUTSCHLER / Conformational Isomerism in Drug Ac tion: Does the Free Energy of Binding Induce the Pharmacophoric Confor- mation of Semi-Rigid Muscarinic Agonists? 179 G. KA TO and B. TA TTRIE / Studies on the Cholinergic Receptor of Squid Optic Ganglia 189 ARTHUR CAMERMAN and NORMAN CAMERMAN / Stereochemical Similarities in Chemically Different Antiepileptic Drugs 213 HA VEN S. ALDRICH and LEMONT B. KIER / Molecular Orbital Calculations on Anti-Epileptic Compounds 229 VI TABLE OF CONTENTS BERNARD TEST A / A Conformational Study of Antihistaminie Pheniramines in Solution 241 NORMAN S. HAM / NMR Studies of Solution Conformations of Physiologieally Aetive Amino-Acids 261 J. J. H. MeDOWELL / The Moleeular Structures of the Phenothiazine Derivatives, Chlorpromazine, Thiethylperazine and Thioridazine, and a Discussion of the Mechanism of Action 269 J. FEENEY, G. C. K. ROBERTS, and A. s. V. BURGEN / Conformational Studies on Hormonal Peptides Using Nuclear Magnetie Resonance Spectroscopy 301 w. A. THOMAS / Conformational Studies of Cyclotetradepsipeptides and Analo- gues Related to Serratamolide 313 J.A. RYAN, FLOYD HOVIS, DALE SPANGLER, JANE HYLTON, and RALPH E. CHRISTOFFERSEN / Ab Initio Calculations on Large Molecules Using Mole- cular Fragments. Initial Studies on Prostagiandin PGF lß 319 R. D. CLONEY, I. J. KING, V. M. SCHERR, and A. J. FORGASH / A Molecular Orbital Study of Some Substituted Benzyl Propynyl Ethers as Insecticide Synergists 333 P. S. POR TOGHESE / The Role of Conformation and Configuration in the Inter- action of 4-Phenylpiperidines with Analgetic Receptors 349 GILDA H. LOEW, DON BERKOWITZ, HAREL WEINSTEIN, and SHALOM SREBRENIK / Quantum Chemical Studies ofMorphine-like Opiate Narcotics: Effect of Polar Group Variations 355 w. G. RICHARDS and c. R. GANELLIN / Calculations on Unstable Conforma- tions of Histamine and Methylhistamines 391 ALBER TE PULLMAN / Model Studies on the Conformational Lability and Carbon-binding Abilities of Antibiotie Cyclic Depsipeptides 401 NORMAN CAMERMAN, J. K. FAWCETT, and ARTHUR CAMERMAN / Confor- mational Studies of Thyroid Hormones and Analogues 413 DONALD VOET I Intermoleeular lnteraetions in Adenine. Barbiturate Com- plexes 429 ROBERT B. HERMANN / Theory of Hydrophobie Bonding. IV: Calculation of Hydrophobie Interactions Between Hydrocarbon Molecules 441 R. F. REKKER and G. G. NYS I A Novel Hydrophobie Parameter for Use in Strue- ture Aetivity Relationship (SAR) Studies 457 THOMAS R. KRUGH I Sequence Specifieity in the Interaetion of Aetinomyein D with Deoxydinucleotides as a Model for the Binding of the Drug to DNA 465 CHARLES E. BUGG and HELENE STERNGLANZ I Structural Properties of Purine and Pyrimidine Analogs 473 DONALD J. NELSON, PATRICK J. COZZONE, and OLEG JARDETZKY / 31p_ Nuclear Magnetic Resonanee Study of ATP and ATG-G-Actin: Direet Evi- denee for Pp and Pr Involvement in Nucleotide Binding 501 TADLE OF CONTENTS VII J. B. LE PECQ, M. LE BRET, CH. GOSSE, C. PAOLETTJ, O. CHALVET, and N. DAT XUONG / Interest of Quantum Mechanical Calculations for the Design of Anticancerous Drugs in the Series of Ellipticines 515 SASSON COHEN, ARIEH GOLDSCHMID, GAD SHTACHER, and SHALOM SREBRENIK / Non-Specific Inhalation Stimulants as a Special Case in the Theory of Anesthesia 537 J. BERGES and F. PERADEJORDI / Theoretical Studies on the Reaction Mecha- nism of Cytotoxic Aromatic Nitrogen Mustards 549 J. R. SMYTHIES / The Molecular Structure of the Sodium Channel 573 I. FISCHER-HJALMARS, M. SUNDBOM, and H. VOKAL / On Mechanisms and Treatments of Metal Allergies 583 ERNST D. BERGMANN / Concluding Remarks 587 PREFACE The seventh Jerusalem Symposium has tried to penetrate into a field of research towards which the efforts of a large number of the most variegated modern techniques are conversing: molecular and quantum pharmacology. The hope to elucidate the mode of action of drugs, to establish correlations between the electronic and con formational structures of drugs and their mode of action and level of activity, to derive from these data the nature of the cellular receptors and an understanding of the interaction of the drugs with those receptors - is a strong stimulus to enlarge and deepen the research efforts with the ultimate view to rationalize the design of more efficient and more specific drugs. The Symposium represents an attempt to survey the progress made so far in this respect and the methods and efforts employed in order to arrive at even greater achievements. The presentation of this Symposium differs somewhat from that of the preceding ones. Owing to the political events which disturbed the peace in the Middle East and therefore the normal activities of commerce and industry in Israel at least temporarily, the printing and distribution of this volume were entrusted to the Reidel Publishing Company. We wish to thank them for their very efficient col1aboration and for all their efforts to publish this volume with a minimum delay. Once again we must thank also Baron Edmond de Rothschild for his generosity which makes this series of Symposia possible, and the Israel Academy of Science and Humanities for its support and hospitality. The support of the European Research Office is also gratefully acknowledged. The political and military events of the year have not influenced the serenity and the depth of this Symposium. The name of Jerusalem guarantees that this will be so for aIl the Symposia to come. E. D. BERGMANN B. PULLMAN INTRODUCTORY REMARKS ON PHARMACOLOGICAL RECEPTORS FELIX BERGMANN Dept. 01 Pharmacology, Hebrew University-Hadassah Medical School, Jerusalem, Israel The hypothesis that drugs may accomplish their action by combination with specific receptors was formulated long before experimental methods were available to identify and isolate receptor molecules, but this idea has proved very fruitful for the develop ment of molecular pharmacology. Although successful isolation of receptor proteins has been c1aimed in a few cases, we are still far from the unequivocal identification of receptor units. Most contributions of this symposium will attack the problem of drug-receptor interaction by determination of the most probable structure of the drug in solution, using the methods of physical and theoretical chemistry. Therefore it seems appropriate to survey first some biological aspects of such interactions, keeping in mind that the conditions of living systems place important restrictions on the applicability of theoretical methods. In most cases, drugs enter from an aqueous medium into the biophase to associate with a macromolecular structure containing the receptor - a process resembling complex formation between enzyme and substrate. Since the binding properties of a drug depend inter alia on its size, we shall divide the present discussion into two parts: (l) Interaction of a receptor with sm all molecules (agonists or antagonists), of molecular weights not exceeding a few hundreds. (2) Interaction of receptors with larger molecules, such as peptide hormones, of molecular weights which reach values of several thousands or ten thousands. Small molecules, containing an open chain of atoms, are flexible and may ass urne a large number of conformations. For instance, for acetylcholine (ACh) four stable conformations have been calculated [I]. Pertinent information on small drug mole cules is usually derived for the solid state from X-ray crystallography, and for solu tions from nmr spectra. Molecular orbital calculations by various methods determine the most stable form of the isolated molecule, first in the gaseous state and eventually also in solution. The problem of the most stable conformer of a given drug becomes considerably simplified by introduction of rings which provide a more or less rigid structure. Thus in histamine (1), the imidazole has a rather accurately defined geometry, the only variable being tautomerism between the 1- and 3-NH groups. Therefore it remains only to determine the spatial arrangement ofthe C-C-N side-chain, as given by its torsion angles. Histamine evokes a wide variety of biological reactions: It contracts the smooth musc1e in the bronchi, the stornach and the ileum; it inhibits the contrac tion of the rat myometrium when the latter is stimulated electrically; it enhances secretion of gastric acid and causes atrial tachycardia. If we examine the activity of E. Bergmann and B.Pullman (eds.) , Molecular and Quantum Pharmacology, 1-7. All Rights Reserved Copyright © 1974 by D. Reidel Publishing Company, Dordrecht-Holland 2 FELIX BERGMANN riCH'CH,NH' riCH'CH,NH' HN N ~ V ~ NyH I riCH'CH,NH' MeHCH'CH'NH, HNY N HNV N Me m n histamine derivatives, e.g. 2-methyl- (Il) and 4-methylhistamine (111), we find a separation of activities into two groups, as shown in Table I [2]. Compound II contracts stomach and ileum, but has only a weak influence on the other responses. Conversely, cpd. III inhibits contraction of the myometrium, stimulates gastric secretion and causes atrial tachycardia. This leads to the conclusion that histamine itself can activate two different receptors, H and Hz. The 2-methyl derivative II acts 1 preferentially on H1 and the 4-methyl isomer III on H2• This assumption is supported by the observation that specific antagonists exist for each receptor; For H the so-called 1 antihistaminics of general structure IV, and for H2 burimamide (V), a thiourea deriva tive of imidazole. Cpd. V blocks inter aHa production of gastric acid, following injection of histamine or pentagastrin or induced by feeding, but not the secretion evoked by vagal stimulation [2].
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