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

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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 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/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 α2C-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 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.

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