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Enna SJ, Bennett JP, Burt DR, Creese I, Snyder SH.
“Stereospecificity of interaction of neuroleptic drugs with neurotransmitters and correlation with clinical potency”.
Nature. 1976;263(5575):338-41.
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Abstract
Stereospecificity of interaction of neuroleptics with neurotransmitters and correlation with clinical potency were studied Methods Receptor binding studies were conducted by incubating crude synaptic membrane or total particulate fractions of various b:rain regions with a low concentration of tritiated ligand in the presence or absence of various concentrations of drug, Ligands used and the receptor to which each binds were 3H-y-aminobutyric acid (3H-GABA), the GABA receptor; 3H-dopamine (3H-DA) and 3H haloperidol (3H-H), DA receptor; 3H-naloxone (3H-N) H-dihydro morphine (3H-DHM), opiate receptor; 3H-dihydroalprenOlol (3H- DHA), 13-adrenergic receptor; 3H-5-hydroxytryptamine (3H-5-HT) and H-lysergic acid diethylamide (3H-LSD), 5-HT receptor; 3H-quinuclidinyl benzilate (3H-QNB), muscarinic cholinergic receptor; and 3H-strychnine (3H-S), the glycine receptor. Receptor binding was assayed in the brain region containing the highest density of receptor sites or in whole brain (rat cerebral cortex, forebrain, spinal cord-brains/em, calf striatum). There were no marked stereospecific influence of (+) or (-) butaclamol, a or p-flupenthixal, cis- or trans-thiothixene, on 3H GABA, 3H-N, 3H-DHM, 3H-S, 3H-QNB and 3H-DHA receptor binding. These neuroleptic isomers were extremely potent in competing for 3H-H binding and showed marked stereospecificity. They also showed stereospecificity with respect to 3H-DA binding but were less potent inhibitors. 3H-LSD and 3H-5-HT binding was inhibited stereospecifically and with considerable potency by these neuroleptics. Variations in the relative potencies of fluspirilene, pirnozide clofuperol, benperidol, bromoperidol, spiroperidol, penfluridol trifluperidol, haloperidol, moperone, droperidol, fluanisone, azaperone, pipamperone in reducing 3H-GABA uptake by rat brain synaptosomes correlated well with the relative clinical potenctes of the drugs. There was no correlation between the influence of phenothiazines and related agents trifluoperazine, fluphenazine, triflupromazine, chlorpromazine, chlorpromazine, promazine, Q or p-flupenthixol, cis or trans-thiothixene on GABA uptake and their clinical effects.
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