[H-3]RO 22-1319 (PIQUINDONE) BINDS TO THE D2 DOPAMINERGIC RECEPTOR SUBTYPE IN A SODIUM-DEPENDENT MANNER

Abstract

Ro 22-1319, a novel pyrroloisoquinoline compound, is a potent antipsychotic agent with low potential for extrapyramidal effects and tardive dyskinesia. The specific binding of [3H]Ro 22-1319 to the rat striatal homogenates was examined. The binding of [3H]Ro 22-1319 was critically dependent on the presence of Na+ in the incubation medium. There appeared to be a single saturable binding component for [3H]Ro 22-1319 with a high affinity. The binding sites showed a stereochemical specificity for (-)Ro 22-1319, (+)butaclamol and (.alpha.)flupenthixol. Ro 22-1319 and 3 D2 antagonistic antipsychotics (sulpiride, metoclopramide and molindone) exerted a more potent inhibition of [3H]Ro 22-1319 binding than of [3H]spiroperidol binding, whereas other classical antipsychotics were almost equiopotent at both binding sites. The requirement for Na+ to detect Ro 22-1319 binding was also verified by the use of [3H] spiroperidol binding. The competition curves of Ro 22-1319, sulpiride, metoclopramide and molindone for [3H]spiroperidol binding were shifted to the right by the omission of sodium in the incubation medium, whereas spiroperidol, chlorpromazine and domperidone were equiactive under both conditions. Apparently, Ro 22-1319 has a sulpiride-like property and binds to a D2 dopaminergic receptor subtype in a Na+-dependent manner. Nineteen pyrroloisoquinoline derivatives were also tested for their inhibitory effects on [3H]Ro 22-1319 and [3H] spiroperidol binding. An interesting finding was that small changes in chemical structure modulated the potency at D2 dopaminergic receptor subtypes. The compounds having a nonlipophilic functional group on the basic nitrogen showed a stronger potency at [3H]Ro 22-1319 receptors whereas the compounds having a lipophilic group were nonselective antagonists at both [3H]Ro 22-1319- and [3H]spiroperidol-binding sites. All pyrroloisoquinoline derivatives including Ro 22-6600 showed a Na+ dependency for [3H]spiroperidol-binding sites, indicating that the functional moiety which displays a Na+ dependency may be the pyrroloisoquinoline moiety itself.