Functional evidence for selective dopamine D-1 receptor blockade by SCH 23390.

The selectivity of a new specific dopamine D-1 receptor antagonist SCH 23390, (R)-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin -7-ol hemimaleate, was investigated in functional neurochemical models. Inhibition of the activity of dopamine-stimulated adenylate cyclase in striatal homogenates of the rat represented an effect at dopamine D-1 receptors, whereas reversal of the decrease in electrically-induced release of tritium from striatal slices of the rabbit, preloaded with [3H]dopamine or [3H]choline by apomorphine, represented D-2 pre- and postsynaptic effects, respectively. The selectivity of the methods was checked by using known D-1 and D-2 agonists, SKF 38393 (2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine hydrochloride) and LY 141865 or LY 171555 (racemate and (-)-enantiomer, respectively; trans-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-2H-pyrazolo [3,4-g]quinoline dihydrochloride), respectively. It was found that SCH 23390 competitively inhibited the activity of dopamine-stimulated adenylate cyclase with a Ki-value of 0.004 microM. In contrast to haloperidol, a specific dopamine D-2 antagonist, which inhibited the decline in release of both ligands from preloaded slices induced by apomorphine, SCH 23390 was without effect on this release from slices loaded with [3H]dopamine but had effect on release from slices loaded with [3H]choline, in concentrations 350 times greater than those of haloperidol (IC50 = 0.63 microM). The results confirm the dopamine D-1-selective blockade by SCH 23390, previously shown using dopamine-receptor binding techniques.