title: 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.
authors.affiliation: Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. hedlund@scripps.edu
authors.forename: Peter B
authors.initials: PB
authors.lastname: Hedlund
authors.forename: Marcello
authors.initials: M
authors.lastname: Leopoldo
authors.forename: Silvio
authors.initials: S
authors.lastname: Caccia
authors.forename: Gor
authors.initials: G
authors.lastname: Sarkisyan
authors.forename: Claudia
authors.initials: C
authors.lastname: Fracasso
authors.forename: Giuliana
authors.initials: G
authors.lastname: Martelli
authors.forename: Enza
authors.initials: E
authors.lastname: Lacivita
authors.forename: Francesco
authors.initials: F
authors.lastname: Berardi
authors.forename: Roberto
authors.initials: R
authors.lastname: Perrone
mesh_terms: D000818:Animals; D001831:Body Temperature / Q000187:drug effects / Q000235:genetics; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D048448:Phenylcarbamates / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D011985:Receptors, Serotonin / Q000172:deficiency / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D014520:Urethane / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: C573815:N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide; D048448:Phenylcarbamates; D010879:Piperazines; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; C104425:serotonin 7 receptor; C058422:N,N-methylethylphenylcarbamate; D014520:Urethane