title: 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 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-HT(2A) and 5-HT(7)) 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-HT(2A) and 5-HT(7) receptors. Furthermore, in line with its in vitro actions, it more potently blocks cerebral populations of D(3) versus D(2) receptors.
authors.affiliation: Institut de Recherches Servier, Centre de Recherches de Croissy, Psychopharmacology Department, 125, Chemin de Ronde, 78290 Croissy-sur-Seine, France. mark.millan@fr.netgrs.com
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Millan
authors.forename: Per
authors.initials: P
authors.lastname: Svenningsson
authors.forename: Charles R
authors.initials: CR
authors.lastname: Ashby
authors.forename: Michael
authors.initials: M
authors.lastname: Hill
authors.forename: Martin
authors.initials: M
authors.lastname: Egeland
authors.forename: Anne
authors.initials: A
authors.lastname: Dekeyne
authors.forename: Mauricette
authors.initials: M
authors.lastname: Brocco
authors.forename: Benjamin
authors.initials: B
authors.lastname: Di Cara
authors.forename: Françoise
authors.initials: F
authors.lastname: Lejeune
authors.forename: Nitza
authors.initials: N
authors.lastname: Thomasson
authors.forename: Carmen
authors.initials: C
authors.lastname: Munoz
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Mocaër
authors.forename: Alan
authors.initials: A
authors.lastname: Crossman
authors.forename: Laetitia
authors.initials: L
authors.lastname: Cistarelli
authors.forename: Sylvie
authors.initials: S
authors.lastname: Girardon
authors.forename: Loretta
authors.initials: L
authors.lastname: Iob
authors.forename: Sylvie
authors.initials: S
authors.lastname: Veiga
authors.forename: Alain
authors.initials: A
authors.lastname: Gobert
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002144:Callithrix; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D018492:Dopamine Antagonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D004594:Electrophysiology; D006168:Guinea Pigs; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000502:physiology*; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3