[3H]Ro 22-1319 (piquindone) binds to the D2 dopaminergic receptor subtype in a sodium-dependent manner.

Ro 22-1319, a novel pyrroloisoquinoline compound, is a potent antipsychotic agent with low potential for extrapyramidal effects and tardive dyskinesia. In this study, the specific binding of [3H]Ro 22-1319 to the rat striatal homogenates has been examined. The binding of [3H]Ro 22-1319 was found to be critically dependent on the presence of sodium 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 three 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 equipotent at both binding sites. The requirement for sodium 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. These results suggest that Ro 22-1319 has a sulpiride-like property and binds to a D2 dopaminergic receptor subtype in a sodium-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. Thus, the compounds having a nonlipophilic functional group on the basic nitrogen (Ro 22-1319, Ro 22-3822, etc.) showed a stronger potency at [3H]Ro 22-1319 receptors whereas the compounds having a lipophilic group (Ro 22-6600, etc.) were nonselective antagonists at both [3H]Ro 22-1319- and [3H]spiroperidol-binding sites. However, all pyrroloisoquinoline derivatives including Ro 22-6600 showed a sodium dependency for [3H]spiroperidol-binding sites, indicating that the functional moiety which displays a sodium dependency may be the pyrroloisoquinoline moiety itself.