Abstract
Heterozygous null mutations in the melanocortin-4 receptor (MC4R) cause early-onset obesity in humans, indicating that metabolic homeostasis is sensitive to quantitative variation in MC4R function. Most of the obesity-causing MC4R mutations functionally characterized so far lead to intracellular retention of receptors by the cell's quality control system. Thus, recovering cell surface expression of mutant MC4Rs could have a beneficial therapeutic value. We tested a pharmacological chaperone approach to restore cell surface expression and function of 10 different mutant forms of human melanocortin-4 receptor found in obese patients. Five cell-permeant MC4R-selective ligands were tested and displayed pharmacological chaperone activities, restoring cell surface targeting and function of the receptors with distinct efficacy profiles for the different mutations. Such mutation-specific efficacies suggested a structure-activity relationship between compounds and mutant receptor conformations that may open a path toward personalized therapy. In addition, one of the five pharmacological chaperones restored function to most of the mutant receptors tested. Combined with its ability to reach the central nervous system and its selectivity for the MC4R, this pharmacological chaperone may represent a candidate for the development of a targeted therapy suitable for a large subset of patients with MC4R-deficient obesity.
Footnotes
This work was supported by Amicus Therapeutics (to M.B.); the Canadian Institute for Health Research [Grant 10501] (to M.B.); and a Canada Research Chair in Cell Signaling and Molecular Pharmacology (to M.B.).
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.172098.
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- GPCR
- G protein-coupled receptor
- ER
- endoplasmic reticulum
- PC
- pharmacological chaperone
- MC4R
- melanocortin-4 receptor
- hMC4R
- human melanocortin-4 receptor
- HA
- hemagglutinin
- MTHP
- 2-(2-(2-methoxy-5-nitrobenzylthio)phenyl)-1,4,5,6-tetrahydropyrimidine
- PPPone
- 3-(4-(2-(4-fluorophenyl)-2-(4-methylpiperazin-1-yl)ethyl)piperazin-1-yl)-2-methyl-1-phenylpropan-1-one
- MPCI
- 2-(5-bromo-2-methoxyphenethyl)-N-(N-((1-ethylpiperidin-4-yl)methyl)carbamimi doyl)-3-fluorobenzamide
- DCPMP
- N-((2R)-3(2,4-dichlorophenyl)-1-(4-(2-((1-methoxypropan-2-ylamino)methyl)phenyl)piperazin-1-yl)-1-oxopropan-2-yl)propionamide
- NBP
- 1-(1-(4-fluorophenyl)-2-(4-(4-(naphthalene-1-yl)butyl)piperazin-1-yl)ethyl)-4-methylpiperazine
- PBS
- phosphate-buffered saline
- BSA
- bovine serum albumin
- NDP
- [Nle4,d-Phe7]
- α-MSH
- α-melanocyte stimulating hormone
- HEK
- human embryonic kidney
- D-PBS
- Dulbecco's PBS
- WT
- wild type
- vYFP
- venus yellow fluorescent protein
- SAR
- structure-activity relationship
- THIQ
- tetrahydroisoquinoline
- TM
- transmembrane domain
- EXL
- extracellular loop.
- Received June 30, 2010.
- Accepted September 7, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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