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University Microfilms International 300 North Zeeb Road Ann Arbor, Michigan 40106 USA St. John's Road, Tyler's Green High Wycombe, Bucks, England HP10 8HR 77-31,832 BOSSART, Josef F., 1951- CONFORMATIONALLY RESTRAINED ANALOGS: CYCLOBUTYL ANALOGS OF DOPAMINE AND 6-HYDROXYDOPAMINE. The Ohio State University, Ph.D., 1977 Chemistry, biological University Microf iims intem ationai, Ann Arbor, Michigan 48ioe | CONFORMATIONALLY RESTRAINED ANALOGS: CYCLOBUTYL ANALOGS OF DOPAMINE AND 6-HYDROXYDOPAMINE Dissertation Presented in Partial Fulfillment of the Reouirements for the Dedree Doctor of Philosophy in the Graduate School of The Ohio State University By Josef F* Bossartf B.Sc» Hon, * * * * The Ohio State University 1977 Readind Committee: Approved By Dr, N, Lewis Dr, D, Miller Dr, P, Patil Dr, D, Witiak Adviser Collede of Pharmacy ACKNOWLEDGEMENTS I would like to thank and acknowledge the support and guidance of mu superviser Dr» Duane D» Miller throughout this study. Not only did he help make mu graduate education 3 rewarding oner but I suspect he made it more fun than it was intended to be. I would like to thank Prof, Popat N, Patil for his guidance of the biological portions of this research and his manu helpful discussions. I would like to acknowledge the excellent biological studies of Dr, Robert Ruffolo and Dr, Harold Komiskeu without which this study would not have been complete, I would like to thank Jack Fowble and Ed Fairchild for their contributions to this research as well as the knowledge and friendship they shared with me. 11 VITA November 22» 1951 Born - Montrealr Quebec» Canada 1969-1973 B*Sc. Hon. Chemistry Carleton University Ottawa» Canada 1973-1976 Research Assistant ColleSe of Pharmacy The Ohio State University Columbus» Ohio 1976-1977 Teachins Assistant Collede of Pharmacy The Ohio State University Columbus» Ohio FIELD OF STUDY. Medicinal Chemistry 111 TABLE OF CONTENTS Fade ACKNOWLEDGEMENTS ii VITA i i i LIST OF FIGURES vi LIST OF TABLES vi i INTRODUCTION Pharmacology of 6-hydroxydopamine 5 Pharmacology of Dopamine 19 OBJECTIVES 37 RESULTS AND DISCUSSION Synthetic 42 A) Preparation of cis- and trans- 2(2',4'p5'-trihydroxyphenyl)cyclobutyl- amine hydrobromide (^) and ( 42 B ) Preparation of trans- and cis- 2(3'f4'-dihydroxyphenyl)eyelobutylamine (50) and (51)» and trans- and cis- NfN-dimethyl-2(3',4'-dihydroxyphenyl) cyclobutylamine hydrobromide (52) and ( ^ ) 53 C) Rearrangement of 2»4»5-trimethoxypropi- ophenone 61 Biological A) Pharmacological Assay of ^ and ^ 68 B) Uptake Assay of Analogs ^ and ^ 72 C) Binding Studies of 50» 51» 52 and53 75 IV EXPERIMENTAL 79 Synthetic 81 Biological 102 SUMMARY 106 BIBLIOGRAPHY 108 LIST OF FIGURES Fiaure Title Fade 1 Conformations of Dopamine 24 2 Rotational Considerations of DopaminerSic ASents 27 3 Newman Projections of Several Riaid Analoas 38 4 Reactions of 2-phenalcyclohutalo;<ime 47 5 90 MHz NMR Spectrum of 75 58 6 Temperature Study of 53 60 7 Results of Neurotoxicity Studies of 6-hydroxydopaminef ^ and ^ vivo 69 TT 8 Inhibition of H-Norepinephrine Uptake in vivo by ^ and 49 70 9 Inhibition of H-Norepinephrine Uptake in vitro by 50 and 5jL 73 10 Inhibition of ^H-Dopamine Uptake in vitro by ^ and 51 73 11 Inhibition of ^H-Dopamine Bindina in vitro by 50» 51 » ^ and ^ 77 VI LIST OF TABLES Table Title Fade 1 Effect of 6-hydroxydopamine on catecholamines and serotonin in the Brains of Rats 3 2 Central Neurotransmitter Depletion by 3a and 3b 5 3 The Activity of 6-hydroxydopamine Analogs: Aromatic Substitution Variants 16 4 The Activity of 6-hydroxydopamine Analogs: Side Chain Variants 17 5 The Activity of Dopaminergic Agents on the Neurons of Helix Aspersa 30 6 Effect of Reaction Conditions on Yield of 61 45 7 Chemical Shifts of the Acetamides 67 and 68 50 8 Stereoselectivity in the Reduction of 72 56 9 Chemical Shifts of the Acetamides 73 and 74 56 10 Spectral Data for A and B 62 11 Possible Structures for A 63 12 Uptake Ki Values for 50 and 72 13 Ki Values for 50r 51 r 52 and 53 76 v n INTRODUCTION The Pharmacology of 6-Hydroxydopamine The first appreciation of 6-hydroxydopamine (6-OHDA) (J^) as a natural product arose with the iji vitro studies of Senoh and Witkop in 1959 of the enzymatic and nonenzymatic conversion of dopamine (DA) (2) to norepinephrine Cl,2], Senoh and Witkop isolated a metabolite of labeled dopamine which did not show the requisite ratio for conversion to norepinephrine and which was shown to be 6-OHDA <!)♦ That 6-OHDA was synthesized vivo was demonstrated by the peripheral administration of labeled DA which allowed isolation of labeled 6-OHDA from the urine of the treated rats ♦ ± 2. Studies by Porter and Stone» in the early sixties» of the pharmacological effects of 6-OHDA indicated that unlike other catecholamines it was capable of causing a long term depletion of norepinephrine (NE) from the hearts of dogs and mice [3»4]* This NE depletion was later shown to be ouite general for NE stores in a number of tissues and animals though when injected peripherally 6-OHDA caused no depletion centrally [5»6]« This depletion of NE was dose dependent» low doses (1-3 mg/kg i.v.) caused only temporary depletion 1 2 while larder doses <100 md/ka) caused déplacement and lond term depletion Z71* The depletion of NE by a variety of false neurotransmitters had been well established but the lond lastind depletion caused by 6-OHDA was unioue. This lond term depletion was postulated by Porter and coworkers to ^rise from the ability of 6-OHDA to destroy or irreversibly alter NE bindind sites C33* Shortly thereafter it was shown that 6-OHDA in larde doses caused destruction of the adrenerdic neuron ultrastucture stained for visualization by flourescence spectroscopy [7,8,9], This destruction of neurons by 6-OHDA was shown to be confined to the nerve terminal and had very little effect, except in neonatal mice and rats CIO], on the axon and neuron cell body C8], The specificity of neurotoxicity was shown to be unioue for catecholamine containind neurons, no destuction of cholinerdic neurons or other tissue was observed [8,9]« This same specificity of neurodestuction was shown to be true for the central nervous system [11], While 6-OHDA did not cause neurodestruction of the central neurons when injected peripherally its central application produced a similar lond lastind depletion of dopamine and norepinephrine. No depletion of cholinerdic neurons was noted and serotonerdic fibres showed very little effect. Table 1, C12], Some selectivity is observed between destruction of dopaminerdic and adrenerdic fibres allowind for specificity in central sympathectamy, Table 1 Effect of 6-OHDA on catecholamines and serotonin in the brains of rats (injection of 200 md of 6-OHDA 2 days before sacrifice)« Controls 6-OHDA injected ud/d ud/d % control Dopamine 0*85 0*58 68 Norepinephrine 0*54 0*19 35 Serotonin 0*49 0*43 88 The selectivity of the neurotoxicity peripherally and centrally was shown to be due to the hidhly specific uptake of 6-OHDA into adrenerdic and dopaminerdic neurons C131* That uptake is reouisite for neurotoxicity was demonstrated by the prevention of 6-OHDA induced neurodestruction by pretreatment with uptake blockers such as imipramine and cocaine [14fl5]* This explained why cell bodies and axons» which do not possess uptake mechanisms for 6-OHDA were not subject to destruction* Whether concentration of 6-OHDA into the neuronal granules is reouisite for its neurotoxicity is not clear* Pretreatment with reserpine did not prevent neuronal destruction by 6-0HDA» an indication that dranular concentration is not necessary C161* However it has been shown that 6-OHDA is be concentrated to a small extent in the amine containind granules by a reserpine resistant mechanism [171* As well as havind presynaptic actions 6-OHDA also may effect the postsynaptic receptor* Pretreatment with 6-OHDA caused a decrease in the pressor response of isolated perfused rat mesenteric arteries to NE [18»19], Responses to calcium chloride and KCl were normal, indicating a specific rather than deneral depression.

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