Identification of agonists and antagonists of the human melanocortin-4 receptor from piperazinebenzylamines.
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).
Tran
Joe A
JA
Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., El Camino Real, San Diego, CA 92130, USA.
Pontillo
Joseph
J
Arellano
Melissa
M
White
Nicole S
NS
Fleck
Beth A
BA
Marinkovic
Dragan
D
Tucci
Fabio C
FC
Lanier
Marion
M
Nelson
Jodie
J
Saunders
John
J
Foster
Alan C
AC
Chen
Chen
C
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
D001596:Benzylamines; D010879:Piperazines; D044105:Receptor, Melanocortin, Type 4; D000077489:Piperazine; D000521:alpha-MSH; D000242:Cyclic AMP