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Competitive Inhibition of Catecholamine Uptake in Synaptosomes of Rat Brain by Rigid Bicyclo‐Octanes
Author(s) -
Wong David T.,
Bymaster Frank P.,
Reid Leroy R.
Publication year - 1980
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.1980.tb11225.x
Subject(s) - dopamine , chemistry , dopaminergic , striatum , synaptosome , desipramine , cerebral cortex , catecholamine , medicine , hypothalamus , non competitive inhibition , endocrinology , pharmacology , in vitro , biochemistry , biology , enzyme , hippocampus , antidepressant
Cis‐3‐(3, 4‐dichlorophenyl)‐2‐ N , N ‐dirnethylaminomethyl‐bi‐cyclo‐[2, 2, 2]‐octane hydrochloride (LR5182) inhibited the uptake of dopamine by a synaptosomal fraction of corpus striatum of rat brain with an inhibitor constant (K i value) of 6 nM. Kinetics analysis according to the methods of Lineweaver‐Burk and Dixon revealed a competitive inhibition of dopamine uptake of LR5182. When the uptake of dopamine by the noradrenergic terminals in the synaptosomal fraction of cerebral cortex was selectively abolished by desipramine, LR5182 competitively inhibited the uptake of dopamine by the dopaminergic terminals with a K i value of 19 nM. LR5182 was also a competitive inhibitor of noradrenaline uptake by synaptosomes of hypothalamus and cerebral cortex with, however, one‐third to one‐tenth the effectiveness, as indicated by the larger K i values, 52 and 58 nM, respectively. Structure‐activity studies with LR5182 and related compounds supported the idea that the uptake sites of dopamine favored a gauche conformer.