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Click-Chemistry-Mediated Synthesis of Selective Melanocortin Receptor 4 Agonists
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-10-24 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00353 Daniel Palmer 1 , Juliana P. L. Gonçalves 1 , Louise V. Hansen 1 , Boqian Wu 2 , Helle Hald 1 , Sanne Schoffelen 1 , Frederik Diness 1 , Sebastian T. Le Quement 3 , Thomas E. Nielsen 4, 5, 6 , Morten Meldal 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-10-24 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00353 Daniel Palmer 1 , Juliana P. L. Gonçalves 1 , Louise V. Hansen 1 , Boqian Wu 2 , Helle Hald 1 , Sanne Schoffelen 1 , Frederik Diness 1 , Sebastian T. Le Quement 3 , Thomas E. Nielsen 4, 5, 6 , Morten Meldal 1
Affiliation
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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.
中文翻译：
单击化学介导的选择性黑皮质素受体4激动剂的合成
黑皮质素受体家族的黑皮质素受体4（MC4R）亚型是用于改善代谢功能障碍的治疗的靶标。内源性MC4R激动剂具有关键药效团（HFRW），而肽激动剂的环化通常会增强药效。因此，通过固相点击化学合成了17种环化肽，以开发新颖的，有效的，选择性的MC4R激动剂。使用cAMP测量和转录报告基因检测，我们观察到由环加成反应产生的几种受约束激动剂对MC4R的选择性高于MC3R和MC5R受体亚型（223-至467倍），而不会影响激动剂的效力。EC 50之间也观察到显着差异两种测定的平均值，在比大多数测试化合物引起cAMP水平显着升高的浓度低的浓度下测得的报告子表达水平稳定。总的来说，我们表征了重要元素，这些元素可调节MC4R核心药效基团的活性，并为激动剂筛选提供了仔细选择检测方法的依据。
更新日期：2017-10-25
中文翻译：
单击化学介导的选择性黑皮质素受体4激动剂的合成
黑皮质素受体家族的黑皮质素受体4（MC4R）亚型是用于改善代谢功能障碍的治疗的靶标。内源性MC4R激动剂具有关键药效团（HFRW），而肽激动剂的环化通常会增强药效。因此，通过固相点击化学合成了17种环化肽，以开发新颖的，有效的，选择性的MC4R激动剂。使用cAMP测量和转录报告基因检测，我们观察到由环加成反应产生的几种受约束激动剂对MC4R的选择性高于MC3R和MC5R受体亚型（223-至467倍），而不会影响激动剂的效力。EC 50之间也观察到显着差异两种测定的平均值，在比大多数测试化合物引起cAMP水平显着升高的浓度低的浓度下测得的报告子表达水平稳定。总的来说，我们表征了重要元素，这些元素可调节MC4R核心药效基团的活性，并为激动剂筛选提供了仔细选择检测方法的依据。
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