title: Identification of agonists and antagonists of the human melanocortin-4 receptor from piperazinebenzylamines.
abstract: SAR studies of a series of piperazinebenzylamines resulted in identification of potent agonists and antagonists of the human melanocortin-4 receptor. Thus, the 1,2,3,4-tetrahydroisoquinolin-1-ylacetyl compound 12e and the quinolin-3-ylcarbonyl analogue 12l possessed K(i) values of 6.3 and 4.5 nM, respectively. Interestingly, 12e was a full agonist with an EC(50) value of 31 nM, and 12l was a weak partial agonist (IA=17%) and functioned as an antagonist (IC(50)=300 nM).
authors.affiliation: Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., El Camino Real, San Diego, CA 92130, USA.
authors.forename: Joe A
authors.initials: JA
authors.lastname: Tran
authors.forename: Joseph
authors.initials: J
authors.lastname: Pontillo
authors.forename: Melissa
authors.initials: M
authors.lastname: Arellano
authors.forename: Nicole S
authors.initials: NS
authors.lastname: White
authors.forename: Beth A
authors.initials: BA
authors.lastname: Fleck
authors.forename: Dragan
authors.initials: D
authors.lastname: Marinkovic
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: Alan C
authors.initials: AC
authors.lastname: Foster
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
mesh_terms: D001596:Benzylamines / Q000138:chemical synthesis* / Q000494:pharmacology*; D002460:Cell Line; D000242:Cyclic AMP / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D006801:Humans; D000077489:Piperazine; D010879:Piperazines / Q000138:chemical synthesis / Q000494:pharmacology; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000235:genetics; D013329:Structure-Activity Relationship; D014162:Transfection; D000521:alpha-MSH / Q000032:analysis
chemical_list: D001596:Benzylamines; D010879:Piperazines; D044105:Receptor, Melanocortin, Type 4; D000077489:Piperazine; D000521:alpha-MSH; D000242:Cyclic AMP