Relative activities of SCH 23390 and its analogs in three tests for D 1/DA 1 dopamine receptor antagonism

Abstract

Inhibitory activities of a series of analogs of SCH 23390 ((R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) in which the 7-chloro group was substituted by bromo, fluoro, methyl and methoxy groups, respectively, were compared in three tests for D 1 and DA 1 dopamine (DA) receptor antagonism: inhibition of DA-induced renal vasolidation in the anesthetized dog (DA 1 receptor model), inhibition of DA-stimulated adenylate cyclase in the striatum of adult female rats (D 1 receptor model) and displacement of [ 3H]SCH 23390 in the striatal homogenates of male rats. In addition the D 2 receptor affinity of each of the compounds chosen was assessed via displacement of [ 3H]spiperone binding from rat striatum. S-enantiomers of the Cl and CH 3 analogs were 200- to 700-fold weaker than the respective R-enantiomers in all three tests. The activity of all the R-enatiomers was in the nanomolar range and varied no more than 8-fold in all three tests. The F analog in the ligand binding test was the only exception, which was 30-fold weaker than the C1 analog. All of the R-enantiomers studied showed much weaker affinity for the D 2 receptor, as assessed by displacement of [ 3H]spiperone binding. Similar enantiomer selectivity and parallel affinities of the R-enantiomers in the prototype models for D 1 and DA 1 receptors strengthen the evidence in support of identity between the D 1 and DA 1 dopamine receptors. These results further indicate that displacement of SCH 23390 in the ligand binding test reflects affinity of a compound for D 1 and DA 1 dopamine receptors.