LP-211 is a brain penetrant selective agonist for the serotonin 5-HT₇ receptor

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• 作者：Peter B. Hedlund ; Marcello Leopoldo ; Silvio Caccia ; Gor Sarkisyan ; Claudia Fracasso ; Giuliana Martelli ; Enza Lacivita ; Francesco Berardi ; Roberto Perrone
• 关键词：Serotonin 5-HT₇ receptor ; Agonist ; LP-211 ; RA-7 ; Brain distribution ; Body temperature
• 刊名：Neuroscience Letters
• 出版年：2010
• 出版时间：30 August 2010
• 年：2010
• 卷：481
• 期：1
• 页码：12-16
• 全文大小：214 K

文摘

We have determined the pharmacological profile of the new serotonin 5-HT₇ receptor agonist N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide (LP-211). Radioligand binding assays were performed on a panel of 5-HT receptor subtypes. The compound was also evaluated in vivo by examining its effect on body temperature regulation in mice lacking the 5-HT₇ receptor (5-HT₇^−/−) and their 5-HT₇^+/+ sibling controls. Disposition studies were performed in mice of both genotypes. It was found that LP-211 was brain penetrant and underwent metabolic degradation to 1-(2-diphenyl)piperazine (RA-7). In vitro binding assays revealed that RA-7 possessed higher 5-HT₇ receptor affinity than LP-211 and a better selectivity profile over a panel of 5-HT receptor subtypes. In vivo it was demonstrated that LP-211, and to a lesser degree RA-7, induced hypothermia in 5-HT₇^+/+ but not in 5-HT₇^−/− mice. Our results suggest that LP-211 can be used as a 5-HT₇ receptor agonist in vivo.