PHARMACOLOGICAL STUDIES ON YM992, A NOVEL ANTIDEPRESSANT WITH SELECTIVE SEROTONIN REUPTAKE INHIBITORY AND 5-HT2A RECEPTOR ANTAGONISTIC ACTIVITY

YM992 ((S)-2-[[(7-fluoro-4-indanyl)oxy]methyl]morpholine monohydrochlo ride) is a novel compound that has selective serotonin (5-hydroxytrypt amine, 5-HT) re-uptake inhibition and 5-HT2A receptor antagonistic act ivity in vivo. YM992, fluoxetine and citalopram showed 5-HT uptake inh ibition activity in l-5-hydroxy-tryptophan (l-5-HTP)-treated mice. YM9 92 and trazodone attenuated 5-HT2A/2C receptor agonist-induced head-tw itches in mice, indicating that these drugs had 5-HT2A receptor antago nistic activity. YM992 and amitriptyline were highly active in the mou se 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 def icit of olfactory-bulbectomized rats, whereas citalopram and amitripty line showed an ameliorative effect only after chronic treatment. Altho ugh YM992 has moderate affinity for alpha(1)-adrenoceptors, alpha(1)-a drenoceptor antagonism of YM992 in vivo was 10 times weaker than that of trazodone. These results demonstrate that YM992 has 5-HT uptake inh ibition and 5-HT2A receptor antagonistic activity in vivo, and suggest that YM992 may be a novel antidepressant with high efficacy in clinic al use. (C) 1997 Elsevier Science B.V.