Differentiation of opiate and neuroleptic receptor binding in rat brain

For 6 large series of compounds derived from the piperidine moieties of spiperone, pimozide, haloperidol, pethidine, fentanyl and 4-methocarboxyl-fentanyl, IC 50 values were determined in the opiate and neuroleptic binding assay using [ 3H]-fentanyl and [ 3H]-haloperidol as ligands, respectively. The specificity and difference between both receptors were demonstrated on the basis of several criteria (1) the stereospecificity of the binding (2) the significant correlation between the in vitro activity of the drugs and their pharmacological potency in vivo, notwithstanding some discrepancies which are probably of pharmacokinetic and/or metabolic origin (3) the ability to discriminate between morphinomimetic and neuroleptic drugs by the differential affinity for their specific receptor (4) the structure—activity relationships derived from the in vitro data indicating that the structural requirements for high affinity binding in vitro parallel those for high in vivo potency (5) a demonstration, on the basis of physicochemical principles, of the difference in binding mechanism between morphinomimetics and neuroleptics to their respective receptor.