Obesity-causing mutations of the melanocortin-4 receptor (MC4R) lead to intracellular retention of these receptors; therefore, recovering cell surface expression and signaling could have a beneficial therapeutic value. Rene et al. investigated five different antagonists of MC4R as potential pharmacological chaperones (PCs) that were able to bind the mutant receptor, cause its cell surface expression, and restore its ability to respond to ligand signaling. Each PC had a different selectivity profile for the different mutated forms of MC4R investigated, of which there are 80 known mutations in early-onset obesity in humans, suggesting that pharmacogenomics may play an important role in the establishment of PCs as therapeutics. N-((2R)-3(2,4-dichlorophenyl)-1-(4-(2-((1-methoxypropan-2-ylamino)methyl)phenyl)piperazin-1-yl)-1-oxopropan-2-yl)propionamide (DCPMP) is one PC that restored the function of most of the mutant MC4 receptors investigated. Combined with its ability to reach the central nervous system and its selectivity for MC4R, this PC may represent a candidate for the development of targeted therapy suitable for patients with MC4R-deficient obesity. It is noteworthy that some PCs also enhanced cell surface expression and signaling of wild-type MC4R, suggesting that PC treatment could possibly be useful for the treatment of obesity in patients with normal MC4Rs.
See article at J Pharmacol Exp Ther 2010, 335:520–533.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics