Identification of agonists and antagonists of the human melanocortin-4 receptor from piperazinebenzylamines

Joe A Tran; Joseph Pontillo; Melissa Arellano; Nicole S White; Beth A Fleck; Dragan Marinkovic; Fabio C Tucci; Marion Lanier; Jodie Nelson; John Saunders; Alan C Foster; Chen Chen

doi:10.1016/j.bmcl.2004.10.096

Identification of agonists and antagonists of the human melanocortin-4 receptor from piperazinebenzylamines

Bioorg Med Chem Lett. 2005 Feb 1;15(3):833-7. doi: 10.1016/j.bmcl.2004.10.096.

Authors

Joe A Tran¹, Joseph Pontillo, Melissa Arellano, Nicole S White, Beth A Fleck, Dragan Marinkovic, Fabio C Tucci, Marion Lanier, Jodie Nelson, John Saunders, Alan C Foster, Chen Chen

Affiliation

¹ Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., El Camino Real, San Diego, CA 92130, USA.

PMID: 15664867
DOI: 10.1016/j.bmcl.2004.10.096

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).

MeSH terms

Benzylamines / chemical synthesis*
Benzylamines / pharmacology*
Cell Line
Cyclic AMP / analysis
Dose-Response Relationship, Drug
Humans
Piperazine
Piperazines / chemical synthesis
Piperazines / pharmacology
Receptor, Melanocortin, Type 4 / agonists*
Receptor, Melanocortin, Type 4 / antagonists & inhibitors*
Receptor, Melanocortin, Type 4 / genetics
Structure-Activity Relationship
Transfection
alpha-MSH / analysis

Substances

Benzylamines
Piperazines
Receptor, Melanocortin, Type 4
Piperazine
alpha-MSH
Cyclic AMP