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

Abstract

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 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 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/D₂ 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 α_2C-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 α_2C-adrenoceptors, 5-HT_2A and 5-HT₇ receptors. Furthermore, in line with its in vitro actions, it more potently blocks cerebral populations of D₃ versus D₂ receptors.