TY - JOUR
T1 - Click-Chemistry-Mediated Synthesis of Selective Melanocortin Receptor 4 Agonists
AU - Palmer, Daniel
AU - Gonçalves, Juliana P.L.
AU - Hansen, Louise V.
AU - Wu, Boqian
AU - Hald, Helle
AU - Schoffelen, Sanne
AU - Diness, Frederik
AU - Le Quement, Sebastian T.
AU - Nielsen, Thomas E.
AU - Meldal, Morten
PY - 2017
Y1 - 2017
N2 - The melanocortin receptor 4 (MC4R) subtype of the melanocortin receptor family is a target for therapeutics to ameliorate metabolic dysfunction. Endogenous MC4R agonists possess a critical pharmacophore (HFRW), and cyclization of peptide agonists often enhances potency. Thus, 17 cyclized peptides were synthesized by solid phase click chemistry to develop novel, potent, selective MC4R agonists. Using cAMP measurements and a transcriptional reporter assay, we observed that several constrained agonists generated by a cycloaddition reaction displayed high selectivity (223- to 467-fold) toward MC4R over MC3R and MC5R receptor subtypes without compromising agonist potency. Significant variation was also observed between the EC50 values for the two assays, with robust levels of reporter expression measured at lower concentrations than those effecting appreciable increases in cAMP levels for the majority of the compounds tested. Collectively, we characterized significant elements that modulate the activity of the core pharmacophore for MC4R and provide a rationale for careful assay selection for agonist screening.
AB - The melanocortin receptor 4 (MC4R) subtype of the melanocortin receptor family is a target for therapeutics to ameliorate metabolic dysfunction. Endogenous MC4R agonists possess a critical pharmacophore (HFRW), and cyclization of peptide agonists often enhances potency. Thus, 17 cyclized peptides were synthesized by solid phase click chemistry to develop novel, potent, selective MC4R agonists. Using cAMP measurements and a transcriptional reporter assay, we observed that several constrained agonists generated by a cycloaddition reaction displayed high selectivity (223- to 467-fold) toward MC4R over MC3R and MC5R receptor subtypes without compromising agonist potency. Significant variation was also observed between the EC50 values for the two assays, with robust levels of reporter expression measured at lower concentrations than those effecting appreciable increases in cAMP levels for the majority of the compounds tested. Collectively, we characterized significant elements that modulate the activity of the core pharmacophore for MC4R and provide a rationale for careful assay selection for agonist screening.
U2 - 10.1021/acs.jmedchem.7b00353
DO - 10.1021/acs.jmedchem.7b00353
M3 - Journal article
C2 - 28972753
AN - SCOPUS:85033369785
SN - 0022-2623
VL - 60
SP - 8716
EP - 8730
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 21
ER -