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

作者：Alan S. Horn, Joseph T. Coyle, Solomon H. Snyder · 发表于：PubMed · 年份：1971 · 被引用次数：284 · 研究领域：Neuroscience and Neuropharmacology Research、Neurotransmitter Receptor Influence on Behavior、Pharmacological Receptor Mechanisms and Effects

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: a...