LP-211 is a brain penetrant selective agonist for the serotonin 5-HT(7) receptor

Abstract

We have determined the pharmacological profile of the new serotonin 5-HT(7) 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-HT(7) receptor (5-HT(7)(-/-)) and their 5-HT(7)(+/+) 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-HT(7) 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-HT(7)(+/+) but not in 5-HT(7)(-/-) mice. Our results suggest that LP-211 can be used as a 5-HT(7) receptor agonist in vivo.

Fig. 1

Effects of LP-211 (square symbols) and RA-7 (round symbols) on body temperature in 5-HT₇^+/+ (open symbols) and 5-HT₇^−/− mice (filled symbols). (A) vehicle (10% ethanol in saline); (B) LP-211 and RA-7, 3 mg · kg⁻¹ i.p.; (C) LP-211 and RA-7, 10 mg · kg⁻¹ i.p.; (D) LP-211, 30 mg · kg⁻¹ i.p.; (E) LP-211 30 mg · kg⁻¹ + SB-269970 10 mg · kg⁻¹ i.p.; (F) LP-211 30 mg · kg⁻¹ + WAY 100135 10 mg · kg⁻¹ i.p. For basal values and statistical evaluation see Table 2.

Fig. 2

Mean brain concentrations of LP-211 (A) and the relationship (individual animals) between brain and plasma concentrations (B) after intraperitoneal doses in 5-HT₇^−/− and 5-HT₇^+/+ mice. Values are mean ± S.D. for 5 mice per treatment group.