S32504 is a dopamine D<sub>2</sub> and D<sub>3</sub> receptor agonist which was under development for the treatment of Parkinson's disease but was never marketed. Its route of administration was unspecified.
S32504 acts as a potent and selective agonist of the dopamine D<sub>3</sub> and D<sub>2</sub> receptors, with values of 2.0âÂÂ3.2nM and 2.5âÂÂ398nM, respectively, depending on the assay. It is a preferential agonist of the dopamine D<sub>3</sub> receptor over the dopamine D<sub>2</sub> receptor. The drug showed little affinity for or activity at more than 50other receptors and targets, including the dopamine D<sub>1</sub>, D<sub>4</sub>, and D<sub>5</sub> receptors and the serotonin 5-HT<sub>1A</sub> and 5-HT<sub>2A</sub> receptors, among others. S32504 suppressed the activity of dopaminergic neurons in the ventral tegmental area (VTA) in rodents. In addition, it potently reduced levels of dopamine in the striatum, nucleus accumbens, and frontal cortex, which could be reversed by the dopamine D<sub>2</sub> and D<sub>3</sub> receptor antagonist haloperidol and by the selective dopamine D<sub>2</sub> receptor antagonist L-741,626, but not by the selective dopamine D<sub>3</sub> receptor antagonist S33084.
The drug produces antiparkinsonian effects in rodents and monkeys and antidepressant- and anxiolytic-like effects in rodents. The antiparkinsonian effects of S32504 could be blocked by the dopamine D<sub>2</sub> and D<sub>3</sub> receptor antagonists haloperidol and raclopride and by L-741,626, but not by S33084, suggesting mediation of these actions by the dopamine D<sub>2</sub> receptor and not by the dopamine D<sub>3</sub> receptor. However, the dopamine D<sub>3</sub> receptor appeared to be involved in dopaminergic neuroprotective effects of S32504. The antidepressant- and anxiolytic-like effects of S32504 were blocked by haloperidol, raclopride, and L-741,626 but not by S33084, again suggesting involvement of the dopamine D<sub>2</sub> receptor and not the dopamine D<sub>3</sub> receptor in these effects. In rats treated with the dopamine depleting agent reserpine and monkeys treated with the dopaminergic neurotoxin MPTP, S32504 reversed hypolocomotion. Conversely, in untreated rodents, S32504 produced hypolocomotion over a wide range of doses and did not produce hyperlocomotion at any assessed dose.
Analogues of S32504 with enhanced affinity and selectivity for the dopamine D<sub>3</sub> receptor over the dopamine D<sub>2</sub> receptor have been developed and described.
S32504 was first described in the scientific literature by 1999.
S32504 was being developed for the treatment of Parkinson's disease by Servier in France. It reached the preclinical research stage of development prior to its development being discontinued. No recent development was reported by 2003.