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.

The novel benzopyranopyrrolidine and potential antipsychotic, S16924 ((+)-2-{1-[2-(2,3-dihydro-benzo[1,4] dioxin-5-yloxy)-ethyl]-pyrrolidin-3yl}-1-(4-fluoro-phenyl)-ethanone), displays marked affinity for serotonin (5-HT)_1A, 5-HT_2A and dopamine D₂ receptors. Herein, we show that it also possesses high affinity for the cloned, INI isoform of h5-HT_2C receptors (pK_i=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 (pK_b=7.93) the 5-HT-induced elevation in intracellular levels of Ca²⁺ ([Ca²⁺]_i) in a CHO cell line stably expressing the INI isoform of 5-HT_2C 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 pK_bs of 7.43 and 7.84, respectively, whereas haloperidol was inactive (<5.0 in each case). Applied alone, S16924, 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-HT_2C receptors, the blockade of which may contribute to its distinctive functional profile of activity. [ABSTRACT FROM AUTHOR]