S33138 [N-[4-[2-[(3aS,9bR)-8-Cyano-1,3a,4,9b-tetrahydro[1]- benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenylacetamide], a Preferential Dopamine D3 versus D2 Receptor Antagonist and Potential Antipsychotic Agent. II. A Neurochemical, Electrophysiological an

The novel benzopyranopyrrolidine, S33138 [N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1]benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenylacetamide], is a preferential antagonist of cloned hu-man D3 versus D2L and D2S receptors. In mice, S33138 (0.04–2.5 mg/kg i.p.) increased levels of mRNA encoding c-fos in D3 recep-tor-rich Isles of Calleja and nucleus accumbens more potently than in D2 receptor-rich striatum. Furthermore, chronic (3 weeks) administration of S33138 to rats reduced the number of sponta-neously active dopaminergic neurones in the ventral tegmental area (0.16–10.0 p.o.) more potently than in the substantia nigra (10.0). In primates treated with 1-methyl-4-phenyl-1,2,3,6-tetrahy-dropyridine, antiparkinson actions of the D3/D2 agonist, ropinirole, were potentiated by low doses of S33138 (0.01–0.16 p.o.) but diminished by a high dose (2.5). Consistent with antagonism o