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 D-3 Versus D-2 Receptor Antagonist And Potential Antipsychotic Agent. Ii. A Neurochemical, Electrophysiological And Behavioral Characterization In Vivo

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 human D-3 versus D-2L and D-2S receptors. In mice, S33138 (0.04-2.5 mg/kg i.p.) increased levels of mRNA encoding c-fos in D-3 receptor-rich Isles of Calleja and nucleus accumbens more potently than in D-2 receptor-rich striatum. Furthermore, chronic (3 weeks) administration of S33138 to rats reduced the number of spontaneously 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-tetrahydropyridine, antiparkinson actions of the D-3/D-2 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 of postsynaptic D-3/D-2 sites, S33138 attenuated hypothermia and yawns elicited by the D-3/D-2 agonist 7-OH-DPAT [(+)-7-dihydroxy-2-(di-n-propylamino)-tetralin] in rats, and it blocked (0.01-0.63, s.c.) discriminative properties of PD128,907 [(+)-(4aR, 10bR)-3,4, 4a, 10b-tetrahydro-4-propyl-2H, 5H-[1]benzopyrano-[4,3-b]-1,4-oxazin-9-ol; trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolininecarboxamide]. Suggesting antagonist properties at D-3/D-2 autoreceptors, S33138 prevented (0.16-2.5 s.c.) the inhibitory influence of PD128,907 upon dopamine release in frontal cortex, nucleus accumbens, and striatum and abolished (0.004-0.25 i.v.) its inhibition of ventral tegmental dopaminergic neuron firing. At higher doses, antagonist actions of S33138 (0.5-4.0 i.v.) at alpha(2C)-adrenoceptors were revealed by an increased firing rate of adrenergic perikarya. Finally, antagonism of 5-hydroxytryptamine (5-HT2A and 5-HT7) receptors was shown by blockade of 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane-induced head twitches (0.63-10.0 s.c.) and 5-carboxytryptamine-induced hypothermia (2.5-20.0 i.p.), respectively. In conclusion, S33138 displays modest antagonist properties at central alpha(2C)-adrenoceptors, 5-HT2A and 5-HT7 receptors. Furthermore, in line with its in vitro actions, it more potently blocks cerebral populations of D-3 versus D-2 receptors.