title: Pharmacological studies on YM992, a novel antidepressant with selective serotonin re-uptake inhibitory and 5-HT2A receptor antagonistic activity.
abstract: YM992 ((S)-2-[[(7-fluoro-4-indanyl)oxy]methyl]morpholine monohydrochloride) is a novel compound that has selective serotonin (5-hydroxytryptamine, 5-HT) re-uptake inhibition and 5-HT2A receptor antagonistic activity in vivo. YM992, fluoxetine and citalopram showed 5-HT uptake inhibition activity in l-5-hydroxy-tryptophan (l-5-HTP)-treated mice. YM992 and trazodone attenuated 5-HT2A/2C receptor agonist-induced head-twitches in mice, indicating that these drugs had 5-HT2A receptor antagonistic activity. YM992 and amitriptyline were highly active in the mouse tail suspension test. In contrast, fluoxetine and citalopram showed only a tendency to reduce the immobility time. Single treatment with YM992 as well as trazodone and fluoxetine ameliorated the learning deficit of olfactory-bulbectomized rats, whereas citalopram and amitriptyline showed an ameliorative effect only after chronic treatment. Although YM992 has moderate affinity for alpha1-adrenoceptors, alpha1-adrenoceptor antagonism of YM992 in vivo was 10 times weaker than that of trazodone. These results demonstrate that YM992 has 5-HT uptake inhibition and 5-HT2A receptor antagonistic activity in vivo, and suggest that YM992 may be a novel antidepressant with high efficacy in clinical use.
authors.affiliation: Neuroscience Research, Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Takeuchi
authors.forename: S
authors.initials: S
authors.lastname: Yatsugi
authors.forename: K
authors.initials: K
authors.lastname: Hatanaka
authors.forename: K
authors.initials: K
authors.lastname: Nakato
authors.forename: H
authors.initials: H
authors.lastname: Hattori
authors.forename: R
authors.initials: R
authors.lastname: Sonoda
authors.forename: K
authors.initials: K
authors.lastname: Koshiya
authors.forename: M
authors.initials: M
authors.lastname: Fujii
authors.forename: T
authors.initials: T
authors.lastname: Yamaguchi
mesh_terms: D000818:Animals; D015283:Citalopram / Q000494:pharmacology / Q000627:therapeutic use; D005473:Fluoxetine / Q000494:pharmacology / Q000627:therapeutic use; D007858:Learning / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D009025:Morpholines / Q000494:pharmacology* / Q000627:therapeutic use; D009830:Olfactory Bulb / Q000502:physiology / Q000601:surgery; D010095:Oxotremorine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D014202:Tremor / Q000139:chemically induced / Q000188:drug therapy
chemical_list: D015283:Citalopram; D005473:Fluoxetine; D009025:Morpholines; D010095:Oxotremorine; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; C105748:lubazodone hydrochloride