Characterisation of the selective 5-HT_1B receptor antagonist SB-616234-A (1-[6-(cis-3,5-dimethylpiperazin-1-yl)-2,3-dihydro-5-methoxyindol-1-yl]-1-[2′-methyl-4′

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• 作者：Lee A. Dawson ; Zoë ; A. Hughes ; Kathryn R. Starr ; James D. Storey ; Letizia Bettelini ; Fabrizio Bacchi ; Roberto Arban ; Alessandro Poffe ; Sergio Melotto ; James J. Hagan and Gary W. Price
• 关键词：5-HT (serotonin) ; 5-HT_1B receptor ; Microdialysis ; Forced swim test ; Pup vocalisation test ; Human threat test
• 刊名：Neuropharmacology
• 出版年：2006
• 出版时间：June 2006
• 年：2006
• 卷：50
• 期：8
• 页码：975-983
• 全文大小：422 K

文摘

The 5-HT_1B receptor has attracted significant interest as a potential target for the development of therapeutics for the treatment of affective disorders such as anxiety and depression. Here we present the in vivo characterisation of a novel, selective and orally bioavailable 5-HT_1B receptor antagonist, SB-616234-A (1-[6-(cis-3,5-dimethylpiperazin-1-yl)-2,3-dihydro-5-methoxyindol-1-yl]-1-[2′-methyl-4′-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methanone hydrochloride). SB-616234-A reversed the 5-HT_1/7 receptor agonist, SKF-99101H-induced hypothermia in guinea pigs in a dose related manner with an ED₅₀ of 2.4 mg/kg p.o. Using in vivo microdialysis in freely moving guinea pigs, SB-616234-A (3–30 mg/kg p.o.) caused a dose-related increase in extracellular 5-HT in the dentate gyrus. Evaluation of antidepressant- and anxiolytic-like effects of this 5-HT_1B receptor antagonist was performed in a variety of models and species. SB-616234-A produced a decrease in immobility time in the mouse forced swim test; an effect suggestive of antidepressant activity. Furthermore, SB-616234-A produced dose-related anxiolytic effects in both rat and guinea pig maternal separation-induced vocalisation models with an ED₅₀ of 1.0 and 3.3 mg/kg i.p., respectively (vs fluoxetine treatment ED₅₀ = 2.2 mg/kg i.p. in both species). Also a significant reduction in posturing behaviours was observed in the human threat test in marmosets; an effect indicative of anxiolytic activity. In summary, SB-616234-A is a novel, potent and orally bioavailable 5-HT_1B receptor antagonist which exhibits a neurochemical and behavioural profile that is consistent with both anxiolytic- and antidepressant-like activity in a variety of species. Taken together these data suggest that SB-616234-A may have therapeutic efficacy in the treatment of affective disorders.