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.
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001058:Apomorphine / Q000494:pharmacology; D001552:Benzazepines / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D002794:Choline / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004558:Electric Stimulation; D006220:Haloperidol / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects*; D017447:Receptors, Dopamine D1
D014150:Antipsychotic Agents; D001552:Benzazepines; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D000262:Adenylyl Cyclases; D006220:Haloperidol; D001058:Apomorphine; D002794:Choline; D004298:Dopamine