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

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.