Catecholamine uptake by synaptosomes from rat brain. Structure-activity relationships of drugs with differential effects on dopamine and norepinephrine neurons.

A number of centrally active drugs, including antiparkinsonian agents, antihistamines, tricyclic antidepressants, and phenothiazines, inhibit catecholamine uptake into synaptosomes prepared from various areas of rat brain. Many of these drugs have markedly differing affinities for the dopamine neurons of the corpus striatum as compared to the norepinephrine neurons in other brain regions. All drugs examined inhibit catecholamine uptake into hypothalamic synaptosomes competitively, but are noncompetitive inhibitors in the corpus striatum. In both brain areas, uptake inhibition appears to be reversible. In a series of drugs, certain structural features are related to the relative selectivity toward norepinephrine or dopamine neurons. Replacement of an alkylamino side chain by a tropine ring system enhances affinity for the dopamine neurons, as does a relative lack of constraint of the aromatic ring. The antidepressant drugs imipramine and amitriptyline are affected oppositely by N -demethylation. While N -demethylation of imipramine increases its affinity for hypothalamic catecholamine synaptosomes 20-fold, N -demethylation of amitriptyline reduces the inhibition of hypothalamic catecholamine uptake 24-fold. Such structure-activity relationships may facilitate the development of drugs with a high degree of selectivity, respectively, for dopamine and norepinephrine neurons. ACKNOWLEDGMENTS We wish to thank the following companies for donations of drugs, listed alphabetically: amytriptyline hydrochloride (Merck Sharp & Dohme); benztropine mesylate (Merck Sharp & Dohme); biperiden hydrochloride (Knoll Pharmaceutical Company); BS 6825, 7039, 7042, 7715, and 7723 (Brocades-Stheeman); carbinoxamine maleate (McNeil Laboratories, Inc.); carphenazine dimaleate (Wyeth Laboratories, Inc.); chlorcyclizine hydrochloride (Burroughs Wellcome and Company); chlorpheniramine maleate (Schering Corporation); chlorpromazine hydrochloride (Smith Kline & French Laboratories); cyclizine hydrochloride (Burroughs Wellcome and Company); cycrimine hydrochloride (Eli Lilly and Company); deptropine citrate (Brocades-Stheeman); desipramine hydrochloride (Geigy Chemical Corporation); diethazine hydrochloride (Smith Kline & French Laboratories); diphenhydramine hydrochloride (Parke Davis and Company); diphenylpyraline hydrochloride (Smith Kline & French Laboratories); doxepin hydrochloride (Charles Pfizer and Company); ethopropazine hydrochloride (Warner-Lambert Research Institute); fenazoxine hydrochloride (Riker Laboratories); hyoscine hydrochloride (Smith Kline & French Laboratories); imipramine hydrochloride (Geigy Chemical Corporation); mepazine hydrochloride (Chemische Fabrik Promonta G.m.b.H.); methixene hydrochloride (Dr. A. Wander, Ltd); nortriptyline hydrochloride (Eli Lilly and Company); orphenadrine hydrochloride (Riker Laboratories); phenindamine tartrate (Hoffman-La Roche, Inc.); procyclidine hydrochloride (Burroughs Wellcome and Company); propiomazine hydrochloride (Wyeth Laboratories, Inc.); protriptyline hydrochloride (Merck Sharp & Dohme); pyrathiazine hydrochloride (Upjohn Company); trihexphenidyl hydrochloride (Lederle Laboratories). We would like to thank Dr. Donald Coffey for his advice on some of the kinetic aspects of this work, and also Miss Molly Ruble for her technical assistance.