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

Daniel Palmer; Juliana P.L. Gonçalves; Louise V. Hansen; Boqian Wu; Helle Hald; Sanne Schoffelen; Frederik Diness; Sebastian T. Le Quement; Thomas E. Nielsen; Morten Meldal

doi:10.1021/acs.jmedchem.7b00353

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

Daniel Palmer^*, Juliana P.L. Gonçalves, Louise V. Hansen, Boqian Wu, Helle Hald, Sanne Schoffelen, Frederik Diness, Sebastian T. Le Quement, Thomas E. Nielsen, Morten Meldal

^*Corresponding author for this work

Department of Chemistry

13 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	60
Issue number	21
Pages (from-to)	8716-8730
Number of pages	15
ISSN	0022-2623
DOIs	https://doi.org/10.1021/acs.jmedchem.7b00353
Publication status	Published - 2017

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@article{78285d91edbb4613a8fc24ff0e834380,

title = "Click-Chemistry-Mediated Synthesis of Selective Melanocortin Receptor 4 Agonists",

abstract = "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.",

author = "Daniel Palmer and Gon{\c c}alves, {Juliana P.L.} and Hansen, {Louise V.} and Boqian Wu and Helle Hald and Sanne Schoffelen and Frederik Diness and {Le Quement}, {Sebastian T.} and Nielsen, {Thomas E.} and Morten Meldal",

year = "2017",

doi = "10.1021/acs.jmedchem.7b00353",

language = "English",

volume = "60",

pages = "8716--8730",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "21",

}

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 -

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

Abstract

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