This dissertation has been microfilmed exactly as received 69-16,652 GHOURI, Mohammad Sarfraz Khan, 1940·­ CHEMISTRY AND PHARMACOLOGY OF ADRENERGIC BLOCKING AGENTS. University of Hawaii, Ph.D., 1969 Pharmacology University Microfilms, Inc., Ann Arbor, Michigan CHEMISTRY AND PHARMACOLOGY OF ADRENERGIC BLOCKING AGENTS A DISSERTATION SUBMITTED TO THE GRADUATE DIVISION OF THE UNIVERSITY OF HAWAII IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY IN PHARMACOLOGY JANUARY 1969 By 1-- r ((I. f f LO 11 Mohammad S~ K!' Ghour1. Dissertation Committee: Thomas J. Haley, Chairman Louis J. Casarett Daniel D. Palmer Lawrence H. Piette Martin D. Rayner ACKNOWLEDGEMENT The only wisdom I have displayed in this study was in the choice of my professors who tmpressed upon me the importance of human relations in molding a career. It is with deep sense of gratitude that I wish to express my appreciation to the members of the Dissertation Committee for their guidance and valuable suggestions. I am deeply indebted to the East-West Center for financial support and for providing a unique opportunity to participate in an international program for Cultural and Technical Interchange. Appreciation are expressed to many others in the Department of Pharmacology. I am particularly grateful to Mrs. Kathryn Yamashiro for her skill in converting a palimpsest to a legible typescript, and to Mr. Nathan Komesu for his cooperation. My final thanks are due to the following companies for the generous supply of the drugs used in this investigation~ Ciba Pharmaceuticals; Merck, Sharp and Dohme; Eli Lilly and Company; U. S. Vitamins and Pharmaceutical Corporation; Burroughs Wellcome and Company; Warner­ Lambert, Wyeth Laboratories Inc.; McNeil Laboratories; Sterting­ Winthrop, and Smith, Kline and French Laboratories. CHEMISTRY AND PHARMACOLOGY OF ADRENERGIC BLOCKING AGENTS A dissertation submitted to the Graduate Division of the University of Hawaii in partial fulfillment of the requirements for the degree of Doctor of Philosophy. ABSTRAGr Studies on the isolated rabbit ileum indicate that this preparation reacts differently to stimulation or blockade of the alpha or beta adrenergic receptors, and thus may be used as a differentiation test object to ascertain the type of receptor involved in the response obtained. This preparation can also be used to differentiate between the drugs that produce their effects by releasing norepinephrine. This tissue is also suitable for demonstrating nonspecific musculotropic actions of drugs. The hormone treated rabbit uterus had alpha and beta adrenergic receptors, and stimulation of the former results in contraction and the latter in relaxation. During the course of study on sympathomimetic drugs, a peculiar observation was made that cyclopentamine effectively blocked isoproterenol-induced inhibition on the ileal and the uterine preparations. Cyclopentamine-induced beta receptor blockade was not to be expected since the structure of this drug had none of the characteristic features of the known beta receptor blocking agents. This finding not only points out that the current hypotheses regarding the structure-activity relationships of adrenergic drugs are inadequate but also makes it imperative that any further speculations on the ~ structure-activity relationships in adrenergic drugs and thereby on the chemical nature of adrenergic receptors ~t consider the dynamic nature of the structures of drug, receptor and the receptor environment. MOreover, it may be stressed that the drug molecule as a whole determines the nature of the biological activity of the drug, and the receptor environment should not be considered irrelevant in any receptor-dependent pharmacological activity. It seems that cyclopentamine has the ability to produce beta receptor blockade by directly acting at beta adrenergic receptor as well as by causing a change in the degree of influence of the receptor environment on the beta receptor activity. Cyclopentamine also provides an indirect evidence that the beta receptor activity is susceptible to the dynamic changes occurring in the vicinity of the receptor. The beta receptor blocking action of cyclopentamine, therefore, suggests a new approach to adrenergic mechanisms, and provides a new basic structure for the development of beta receptor blocking drugs. The presence of an isopropyl group on the amino nitrogen and the catechol hydroxyl groups were found to increase specificity with resultant increase in the intrinsic activity at beta receptor. But these groups do not seem to define absolute structural requirements for activity at beta receptors. However, the presence of the beta hydroxyl group in beta receptor agonists is essential. The only essential requirement for intrinsic activity at alpha adrenergic receptor is the presence of the ethylamine side chain. Substitution in the ethylamine moiety invariably decreases alpha receptor stimulating activity. With large substituent groups alpha v receptor blocking property is obtained. It appears that an aromatic ring is required for alpha adrenergic receptor blocking action since no aliphatic amine was found to have alpha receptor blocking activity. Substitution in the ethyl moiety decreases affinity for alpha receptor, but produces sympathomimetic amines that act by releasing norepinephrine. TABLE OF CONTENTS PAGE ACi<Ncm.EDGEMENT . • · · • · · · · · · · · · ii ABS'rRAGr . · · · · · · · ··· · iii LIST OF TABLES • . · • . · · · · · • ·· · · · · · viii LIST OF ILLUS'rRATIONS . · · · · · · · · · · · · · x CHAPTER I. INTRODUGrION ·· · · · · · · · · · · 1 A. Review of Literature • · · ··· 1 l. Preparations with alpha receptors • 6 2. Preparations with beta receptors · · 8 3. Structure-Activity relationships of alpha receptor blocking agents · · · · · · · · · · · · 9 (a) Ergot alkaloids 10 (b) Yohimbine and related alkaloids 14 (c) Benzodioxans · · 14 (d) Phenoxyethylamines· · · · · 17 (e) Beta-haloalkylamines · · · · 18 (f) Phenoxybenzamines ·· · · 31 (g) Dibenzazepines · · 40 (h) Pyrrolidines · · 41 (i) Piperazines · · · 43 (j) Tetrazoles · · ·· · · • 49 (k) Imidazolines· · · ···· · · · · 52 4. Structure-Activity relationships of beta-receptor blocking agents • 56 5. Stereochemical aspects • ·· · 72 6. Effects of adrenergic receptors· · · · blocking agents on the nervous system · • 75 7. Antiarrhythmic properties· ·· ·· · ·• 79 8. Metabolic effects of adrenergic · ·· receptors blocking agents 85 B. Statement of the Problem · • · • · · 93 C. Objectives of the Studies · · ·· 97 vii TABLE OF CmlTENTS (Cont'd) PAGE CHAPTER II. METHODS AND MATERIALS •• . · .. · ... 96 1. Introduction ••••••••••••• 96 2. Selection of tissue preparations ••••• 96 (a) Isolated ileal preparation 99 (b) Isolated uterine preparation •• 99 3. Experimental details 101 (a) Determination of alpha receptor stimulating property •••••• 103 (b) Determination of alpha receptor blocking property •••••• 104 (c) Determination of beta receptor stimulating property ••••• 105 (d) Determination of beta receptor blocking property ••••••••• 105 4. Analysis of results •• 106 5. Drugs and solutions •• 111 CHAPTER III. RESULTS, DISCUSSIONS AND CONCLUSIONS 115 1. Basis for interpretation and integration data . • · 115 2. Alkylethylamine series · ·· · · 118 3. Phenylalkylamine series · · . · · ·· · 123 4. Phenylalkanolamine series· · · .. · 129 5. Heterocyclic compounds • · · · · 132 6. Congeners of dichloroisoproterenol • · · • 137 CHAPTER IV. SUMMARY . ... .. 163 APPENDIX . .. .. .. 168 BIBLIOGRAPHY .. .. .... ·. 173 LIST OF TABLES TABLE PAGE I COMPARISON OF ACTIONS OF NOREPINEPHRmE AND ISOPROTERENOL AND THE TYPES OF ADRENERGIC RECEPTORS IN VARIOUS TISSUES ••••••••••• 3 II ADRENERGIC BLOCKING DRUGS ••• 11 III STRUCTURE-ACTIVITY RELATIONSHIPS m PHENYLALKANOLAMINES ••• ••• 57 IV STRUCTURE-ACTIVITY RELATIONSHIPS IN SULFONAMIDO SUBSTITUTED PHENYLALKANOLAMINES . ... 65 V COMPARISON OF POTENCY OF ALPHA-RECEPTOR BLOCKING AGENTS AND THEIR ISOMERS •••• . .. 74 VI COMPARISON OF ALPHA-RECEPI:OR STIMULATING PROPERTIES •••••••••••• . 119 VII POTENCY COMPARISON OF ALPHA-RECEPTOR STD1ULANTS••••••••••• 120 VIII STRUCTURE-ACTIVITY RELATIONSHIPS m ALKYLETHYLAMmE SERIES ••••••• 122 IX COMPARISON OF ALPHA-RECEPI:OR BLOCKING PROPERTIES ON ISOLATED RABBIT ILEUM •• •••••••••••••• 124 X COMPARISON OF ALPHA RECEPTOR BLOCKING PROPERTIES ON ISOLATED RABBIT UTERUS •••••••••••••••• 125 XI POTENCY COMPARISON OF ALPHA-RECEPTOR BLOCKING AGEN'TS •••••••••••• ••••• 126 XII STRUCTURE-ACTIVITY RELATIONSHIPS m PHENYLALKYLAMINE SERIES •••• 127 XIII STRUCTURE-ACTIVITY RELATIONSHIPS IN PHENYLALKANOLAMINE SERIES •••• •• . .. 131 XIV COMPARISON OF SLOPE RATIOS AND SLOPE FACTORS FOR. ALPHA-RECEPTOR STIMULANTS . .. 138 xv COMPARISON OF SLOPE RATIOS AND SLOPE FACTORS FOR ALPHA-RECEPTOR BLOCKING AGENTS ON ISOLATED ILEUM ••••• 139 ix LIST OF '!ABLES (Cont'd) '!ABLE PAGE XVI COMPARISON OF SLOPE RATIOS AND SLOPE FACTORS FOR ALPHA-RECEPTOR BLOCKING AGENTS ON ISOLATED UTERUS ••••• . .. 140 XVII COMPARISON OF BETA RECEPTOR BLOCKING PROPERTIES •••• · . .. 143 XVIII POTENCY COMPARISON OF BETA RECEPTOR BLOCKING AGENTS •• · ... ..... .. 144 XIX COMPARISON OF BETA RECEPTOR STIMULATING PROPERTIES 148 xx POTENCY COMPARISON OF BETA RECEPTOR STIMULANTS ••• ·... ... ... 149 XXI STRUCTURE-ACTIVITY RELATIONSHIPS OF CONGENERS OF DICHLOkOISOPROTERENOL 151 XXII COMPARISON OF SLOPE RATIOS AND SLOPE FACTORS FOR BETA RECEPTOR STIMULANTS 155 XXIII COMPARISON OF SLOPE RATIOS AND SLOPE FACTORS FOR BETA RECEPTOR BLOCKING AGENTS . 156 LIST OF ILLUSTRATIONS FIGURE