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J Med Chem. 2017 Nov 9;60(21):8716-8730. doi: 10.1021/acs.jmedchem.7b00353. Epub 2017 Oct 24.

Click-Chemistry-Mediated Synthesis of Selective Melanocortin Receptor 4 Agonists.

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CECB, Department of Chemistry, University of Copenhagen , Universitetsparken 5, 2100 Copenhagen, Denmark.
Aquaporin A/S , Ole Maaløes Vej 3, 2200 Copenhagen, Denmark.
CMC API Development, Novo Nordisk A/S , Novo Nordisk Park, 2760 Måløv, Denmark.
Protein & Peptide Chemistry, Novo Nordisk A/S , Novo Nordisk Park, 2760 Måløv, Denmark.
Department of Immunology and Microbiology, University of Copenhagen , Blegdamsvej 3B, 2200 Copenhagen, Denmark.
Singapore Centre on Environmental Life Sciences Engineering, Nanyang Technological University , 60 Nanyang Drive, SG 637551, Singapore.


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.

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