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 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 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 receptor-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 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 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 of postsynaptic D3/D 2 sites, S33138 attenuated hypothermia and yawns elicited by the D3/D2 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 D3/D2 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 α2C-adrenoceptors were revealed by an increased firing rate of adrenergic perikarya. Finally, antagonism of 5-hydroxytryptamine (5-HT 2A 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 α2C-adrenoceptors, 5-HT2A and 5-HT7 receptors. Furthermore, in line with its in vitro actions, it more potently blocks cerebral populations of D3 versus D2 receptors. Copyright © 2008 by The American Society for Pharmacology and Experimental Therapeutics.