title: Biochemical profile of YM992, a novel selective serotonin reuptake inhibitor with 5-HT2A receptor antagonistic activity.
abstract: YM992, (S)-2-[[(7-fluoro-4-indanyl)oxy]methyl]morpholine monohydrochloride, exhibited the biochemical profile of a selective serotonin (5-HT) reuptake inhibitor (SSRI) with 5-HT2A receptor antagonistic activity. YM922 showed the same high affinity as fluoxetine against the 5-HT reuptake site (Ki = 21 nM) and a similar affinity to that of crazodone against the 5-HT2A receptor (Ki = 86 nM). In other receptor binding studies, an affinity for the adrenergic alpha 1 receptor (Ki = 200 nM) and 5-HT2C receptor (Ki = 680 nM) was observed. In a monoamine uptake study, YM992 showed a selective 5-HT uptake inhibition (IC50 = 0.15 microM), but only very weakly inhibited both noradrenaline (NA) and dopamine (DA) uptake (IC50 = 3.1 microM (NA), > 10 microM (DA)). YM992 was also found to potently inhibit the aggregation of human platelets (IC50 = 1.9 microM), 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.
authors.affiliation: Neuroscience and Gastrointestinal Research Laboratories, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Hatanaka
authors.forename: T
authors.initials: T
authors.lastname: Nomura
authors.forename: K
authors.initials: K
authors.lastname: Hidaka
authors.forename: H
authors.initials: H
authors.lastname: Takeuchi
authors.forename: S
authors.initials: S
authors.lastname: Yatsugi
authors.forename: M
authors.initials: M
authors.lastname: Fujii
authors.forename: T
authors.initials: T
authors.lastname: Yamaguchi
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D015306:Biogenic Monoamines / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D015306:Biogenic Monoamines; D009025:Morpholines; D010975:Platelet Aggregation Inhibitors; D017981:Receptors, Neurotransmitter; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; C105748:lubazodone hydrochloride