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I I 71-22 ,*+69 EFFLAND, Richard Charles, 1942- SYNTHETIC AND PHARMACOLOGICAL STUDIES OF AGENTS AFFECTING PERIPHERAL ADRENERGIC ACTIVITY. The Ohio State University, Ph.D., 1971 Chemistry, pharmaceutical University Microfilms, A XEROX Company, Ann Arbor, Michigan THIS DISSERTATION HAS BEEN MICROFILMED EXACTLY AS RECEIVED SYNTHETIC AND PHARMACOLOGICAL STUDIES OF AGENTS AFFECTING PERIPHERAL ADRENERGIC ACTIVITY DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University U r Richard CC^Effland, B .S . $ $ $ $ $ $ The Ohio State University 1971 Approved by / Adviser Oollege of Pharmacy ACKNOWLEDGMENTS I wish to express my sincere appreciation to Professor Jules B. LaPidus, for his guidance and support as adviser throughout this study Professor Popat N. Patil, for his patience, time, and assis tance in carrying out the pharmacological studies Professor Donald T. Witiak, for his encouragement and assis tance during and prior to these studies My Mother and Grandmother, for their many sacrifices that have made this possible My wife, Mary Louise, for her encouragement, understanding, and confidence, and to whom, along with my son DuWayne, I dedicate this work. VITA August 26, 1942 ................................................................ Born—Peoria, Illinois 1965..................................................................................... B. S. Pharmacy, The University of Iowa, Iowa City, Iowa 1965-196 6.......................................................................... Teaching Assistant, College of Pharmacy, The Ohio State University, Columbus, Ohio 1966-197 0.......................................................................... NIH Pre-doctoral Fellow, College of Pharmacy, The Ohio State University, Co lumbus, Ohio 1970-1971 ....................................................... .................. Research Assistant, College of Pharmacy, The Ohio State University, Columbus, Ohio FIELDS OF STUDY Major Field: Medicinal Chemistry TABLE OF CONTENTS ACKNOWLEDGMENTS......................................................................................... ii VITA............................................................................................................................. iii LIST OF TABLES.................................................................................................... v LIST OF FIGURES..................................................................... vi INTRODUCTION....................................................................................................... 1 RESULTS AND DISCUSSION A. SYNTHETIC...................................................................................... 24 B. BIOLOGICAL............................................................ 66 EXPERIMENTAL A. SYNTHETIC.................................................................................. 85 B. BIOLOGICAL.................................................................................. 102 SUMMARY...................................................................................................... 106 BIBLIOGRAPHY. .j ............................................................................................ 109 iv LIST OF TABLES Table Page 1. Chemical shifts and coupling constants for the 1- benzylic proton (H^) and 2-methyl protons of the dia- stereomeric l-hydroxy-2-methyl-2,3,4,5-tetrahydro- 3-benzazepines ..................................................................................... 45 2. Proton resonance characteristics of substituted tetrahydro-3-benzazepines ......................................................................... 52 3. Relative activities of isomeric cocaines and related compounds on response of rat vas deferens to (-)- norepinephrine ....................................................................................... 67 4. Norepinephrine potentiating effects of isomeric cocaines and trojJacocaines on rat vas deferens ......................................... 70 5. Relative activities of isomeric cocaines and related compounds on norepinephrine induced contractions of rat vas deferens .......................................................................... 72 6. Relative activities for alpha-adrenergic blockade by atropine related compounds ............................................... 76 v LIST OF FIGURES Figure Page 1. The nrar spectrum of l-hydroxy-2-methyl-2,3,4,5- tetrahydro-3-benzazepine (A) ........................................................... 43 2. The nmr spectrum of l-hydroxy-2-methyl-2,3,4,5- tetrahydro-3-benzazepine (B) ........................................................... 44 3. The nmr spectrum of l-hydroxy-2,3,4,5-tetrahydro- 3-benzazepine .............................................................. 55 4. Log dose-response curves for the norepinephrine potentiating effects of (-)-cocaine, (±)-allops eudoco- caine, and pseudococaine ................................................. 69 5. Dose-response curves for (-)-norepinephrine and pseudoecgonine methyl ester ............................................................ 75 6. Log dose-response curves for alpha-adrenergic blocking activity of homatropine hydrobromide. ..... 77 INTRODUCTION While the pharmacological effects of many adrenergic agents have long been known, the mechanism of action of these substances at the receptor level has remained the object of intensive research. Adrenergic drugs are those chemical compounds that exert an effect on the adrenergic nervous system, or that part of the peripheral autonomic nervous system mediated by the neurochemical hormone norepinephrine. The many pharmacological actions of a number of epinephrine related substances led Ahlquist^ to suggest the I presence of two different types of adrenergic receptors. A series of closely related catecholamines were ranked in order of potency on a variety of tissues and vascular systems. His studies revealed two distinct orders of potencies for the sympathomimetic agents. In one, epinephrine was the most potent and isoproterenol the least. In the other, isoproterenol was the most potent. However, it was also found that these receptors could produce both inhibitory or excitatory action depending upon the tissue. Therefore, classification of the two receptor types as inhibitory or excitatory seemed inappropriate. Ahlquist instead proposed that those receptors toward which epinephrine and norepinephrine were the most active be classified as alpha receptors and those toward which isoproterenol was the most active be classified as beta 1 2 receptors. Alpha receptors were associated primarily with excitatory acti vities except in the intestine where inhibition resulted from stimulation of the alpha receptors. Similarly, stimulation of the beta receptors produced pri marily inhibition, except for myocardial tissue where excitation resulted. Many attempts have been made to define the nature of the adrenergic receptors at the molecular level, and several theories of drug-receptor in teraction have been proposed, such as the ’’Conformational Perturbation 2 Theory’’ of Bernard Belleau. As a basic postulate, it is proposed that the key drug induced change which is significant with respect to a given response is a conformational perturbation of the protein-like molecule which acts as the receptor. This event would serve to transform the receptor from a latent catalytic unit to an active species capable of catalyzing the chemical modifica tion of a substrate molecule forming an integral part of the chemical machi nery underlying contractile processes. In most cases of enzyme activation, it is thought that the interaction of small molecules with regulatory sites in duces specific conformational changes which alter the catalytic efficiency of the enzyme. A similar idea, an "induced fit theory", has been advanced by 3,4 5,6 Koshland. Belleau has suggested that the agonist effect produced by a catecholamine at excitatory adrenergic alpha receptors results from ion-pair formation between the protonated amine head of the agonist and an anionic site on the receptor surface, of which ATP is an integral part. The contractile response is presumed to result from complete charge neutralization at this 3 site. Bloom and Goldman have modified Belleau's adrenergic receptor hy pothesis, and offered an alternative proposal, the "Dynamic Receptor 7 Hypothesis." They envisioned the adrenergic receptors as enzyme-substrate complexes, consisting of a phosphorlytic enzyme and adenosine tri phosphate (ATP). Catecholamine agonists interact with the nucleotide substrate-phosphorolytic enzyme complex in such a manner as to stimulate the rate of phosphorolysis or phosphoryl group transfer reactions of the terminal phosphate group of ATP, with adenosine 5'-diphosphate (ADP) produced. The production of a response by this interaction involves receptor (Enzyme- Substrate) destruction, with a concommitant release of calcium ion, which in turn initiates muscle response. The compatibility of the dynamic receptor hypothesis with existing theories of drug action such as the occupancy 8,9 10 theory, Belleau's conformational perturbation theory, and Paton's rate 11 7 1! theory is also discussed by Bloom and Goldman. More recently, Belleau 13 has revised his original proposal as well as incorporating and rejecting 7 various aspects of Bloom and Goldman's hypothesis. Belleau maintains charge neutralization of the terminal phosphate

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