title: A potent and selective nonpeptide antagonist of the melanocortin-4 receptor induces food intake in satiated mice.
abstract: Optimization on a series of piperazinebenzylamines resulted in analogues with low nanomolar binding at the human MC4 receptor but weak affinity (Ki > 500 nM) at the MC3 receptor. Compound 14c was identified to be a potent MC4R antagonist (Ki = 3.2 nM) with a selectivity of 240-fold over MC3R. It proved to be an insurmountable antagonist in a cAMP assay. Compound 14c potently stimulated food intake in satiated mice when given by intracerebroventricular administration.
authors.affiliation: Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, CA 92130, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Pontillo
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Tran
authors.forename: Stacy
authors.initials: S
authors.lastname: Markison
authors.forename: Margaret
authors.initials: M
authors.lastname: Joppa
authors.forename: Beth A
authors.initials: BA
authors.lastname: Fleck
authors.forename: Dragan
authors.initials: D
authors.lastname: Marinkovic
authors.forename: Melissa
authors.initials: M
authors.lastname: Arellano
authors.forename: Fabio C
authors.initials: FC
authors.lastname: Tucci
authors.forename: Marion
authors.initials: M
authors.lastname: Lanier
authors.forename: Jodie
authors.initials: J
authors.lastname: Nelson
authors.forename: John
authors.initials: J
authors.lastname: Saunders
authors.forename: Sam R J
authors.initials: SR
authors.lastname: Hoare
authors.forename: Alan C
authors.initials: AC
authors.lastname: Foster
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
mesh_terms: D000818:Animals; D001596:Benzylamines / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005247:Feeding Behavior / Q000187:drug effects*; D006801:Humans; D051379:Mice; D010879:Piperazines / Q000494:pharmacology*; D044105:Receptor, Melanocortin, Type 4 / Q000037:antagonists & inhibitors*; D012528:Satiety Response
chemical_list: D001596:Benzylamines; D010879:Piperazines; D044105:Receptor, Melanocortin, Type 4; C030796:benzylamine