A potent and selective nonpeptide antagonist of the melanocortin-4 receptor induces food intake in satiated mice.
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.
Pontillo
Joseph
J
Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, CA 92130, USA.
Tran
Joseph A
JA
Markison
Stacy
S
Joppa
Margaret
M
Fleck
Beth A
BA
Marinkovic
Dragan
D
Arellano
Melissa
M
Tucci
Fabio C
FC
Lanier
Marion
M
Nelson
Jodie
J
Saunders
John
J
Hoare
Sam R J
SR
Foster
Alan C
AC
Chen
Chen
C
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
D001596:Benzylamines; D010879:Piperazines; D044105:Receptor, Melanocortin, Type 4; C030796:benzylamine