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NEUROPHARMACOLOGY

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

Mark J. Millan, Per Svenningsson, Charles R. Ashby, Jr., Michael Hill, Martin Egeland, Anne Dekeyne, Mauricette Brocco, Benjamin Di Cara, Françoise Lejeune, Nitza Thomasson, Carmen Muoz, Elisabeth Mocaër, Alan Crossman, Laetitia Cistarelli, Sylvie Girardon, Loretta Iob, Sylvie Veiga, and Alain Gobert

Psychopharmacology Department, Institut de Recherches Servier, Centre de Recherches de Croissy, Croissy-sur-Seine, Paris, France (M.J.M., A.D., M.B., B.D.C., F.L., L.C., S.G., L.I., S.V., A.G.); Karolinska Institutet, Section of Translational Neuropharmacology, Department of Physiology and Pharmacology, Stockholm, Sweden (P.S., M.E.); Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Jamaica, New York (C.R.A.); Motac Neuroscience Ltd, Williams House, Manchester Science Park, Manchester, United Kingdom (M.H., A.C.); and Therapeutical Division, Institut de Recherches International Servier, Courbevoie Cdx, France (N.T., C.M., E.M.)

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 _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 _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.

Address correspondence to: Dr. Mark J. Millan, Institut de Recherches Servier, Centre de Recherches de Croissy, Psychopharmacology Department, 125, Chemin de Ronde, 78290 Croissy-sur-Seine, France. E-mail: mark.millan{at}fr.netgrs.com

This article has been cited by other articles:

				M. J. Millan, F. Loiseau, A. Dekeyne, A. Gobert, G. Flik, T. I. Cremers, J.-M. Rivet, D. Sicard, R. Billiras, and M. Brocco S33138 (N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1] benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenyl-acetamide), a Preferential Dopamine D3 versus D2 Receptor Antagonist and Potential Antipsychotic Agent: III. Actions in Models of Therapeutic Activity and Induction of Side Effects J. Pharmacol. Exp. Ther., March 1, 2008; 324(3): 1212 - 1226. [Abstract] [Full Text] [PDF]