Biochemical profile of YM992, a novel selective serotonin reuptake inhibitor with 5-HT2A receptor antagonistic activity

YM992, (S)-2-[[(7-fluoro-4-indanyl)oxy]methyl]mo monohydrochloride, exhibited the biochemical profile of a selective serotonin (5-HT) reuptake inhibitor (SSRI) with 5-HT2A receptor antagonistic activity. YM992 showed the same high affinity as fluoxetine against the 5-HT reuptake site (K-i = 21 nM) and a similar affinity to that of trazodone against the 5-HT2A receptor (K-i = 86 nM). In other receptor binding studies, an affinity for the adrenergic alpha(1) receptor (K-i = 200 nM) and 5-HT2C receptor (K-i = 680 nM) was observed. In a monoamine uptake study, YM992 showed a selective 5-HT uptake inhibition (IC50 = 0.15 mu M), but only very weakly inhibited both noradrenaline (NA) and dopamine (DA) uptake (IC50 = 3.1 mu M (NA), > 10 mu M (DA)). YM992 was also found to potently inhibit the aggregation of human platelets (IC50 = 1.9 mu M), revealing antagonistic activity for the 5-HT2A receptor in vitro. Enhanced serotonergic neurotransmission, in particular that mediated by the 5-HT1A receptor, has recently been reported to be important in the long-term treatment of depressive disorders with antidepressants. In addition, some 5-HT1A receptor-mediated responses are known to be potentiated by co-administration of 5-HT2A receptor antagonists. Thus, YM992, having both selective 5-HT reuptake inhibition and 5-HT2A antagonistic activity, might show potent therapeutic activity as a novel antidepressant in comparison with conventional SSRIs. Copyright (C) 1996 Elsevier Science Ltd.