title: Antagonist properties of the novel antipsychotic, S16924, at cloned, human serotonin 5-HT2C receptors: a parallel phosphatidylinositol and calcium accumulation comparison with clozapine and haloperidol.
abstract: The novel benzopyranopyrrolidine and potential antipsychotic, S16924 ((+)-2-[[1-[2-(2,3-dihydrobenzo[ 1,4] dioxin-5-yloxy)-ethyl]-pyrrolidin-3yl]]-1-(4-fluoro-ph enyl)-ethanone), displays marked affinity for serotonin (5-HT)1A, 5-HT2A and dopamine D2 receptors. Herein, we show that it also possesses high affinity for the cloned, INI isoform of h5-HT2c receptors (pKi=8.28) stably expressed in CHO cells. Similarly, clozapine (8.04) was a potent ligand, whereas haloperidol (<6.0) showed low affinity. As demonstrated by fura2-detection, S16924 concentration-dependently abolished (pKb=7.93) the 5HT-induced elevation in intracellular levels of Ca2+ ([Ca2+]i) in a CHO cell line stably expressing the INI isoform of 5-HT2c receptors. Further, as determined by depletion of membrane-bound levels of pre-labelled [3H]phosphatidylinositols ([3H]PI), S16924 concentration-dependently, surmountably and competitively blocked the activation of phospholipase C by 5-HT. This action was expressed with a pA2 of 7.89 according to Schild analysis. Clozapine likewise inhibited 5-HT-induced alterations in [Ca2+]i and [3H]PI levels with pKbs of 7.43 and 7.84, respectively, whereas haloperidol was inactive (<5.0 in each case). Applied alone, S 16924, clozapine and haloperidol modified levels of neither [Ca2+]i nor [3H]PI. In conclusion, in analogy to clozapine, and in contrast to haloperidol, S16924 behaves as a potent and competitive antagonist at h5-HT2c receptors, the blockade of which may contribute to its distinctive functional profile of activity.
authors.affiliation: Institut de Recherches Servier, Psychopharmacology Department, Croissy-sur-Seine, France.
authors.forename: D
authors.initials: D
authors.lastname: Cussac
authors.forename: A
authors.initials: A
authors.lastname: Newman-Tancredi
authors.forename: J P
authors.initials: JP
authors.lastname: Nicolas
authors.forename: J A
authors.initials: JA
authors.lastname: Boutin
authors.forename: M J
authors.initials: MJ
authors.lastname: Millan
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism*; D003024:Clozapine / Q000494:pharmacology; D006224:Cricetinae; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D010716:Phosphatidylinositols / Q000378:metabolism*; D011759:Pyrrolidines / Q000494:pharmacology*; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000235:genetics / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D014162:Transfection; D014316:Tritium
chemical_list: D014150:Antipsychotic Agents; D010716:Phosphatidylinositols; D011759:Pyrrolidines; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; C114530:S 16924; D012702:Serotonin Antagonists; D014316:Tritium; D003024:Clozapine; D006220:Haloperidol; D002118:Calcium