Design of a new peptidomimetic agonist for the melanocortin receptors based on the solution structure of the peptide ligand, Ac-Nle-cyclo[Asp-Pro-dPhe-Arg-Trp-Lys]-NH2
The solution structure of a potent melanocortin receptor agonist, Ac-Nle-cyclo[Asp-Pro-dPhe-Arg-Trp-Lys]-NH2 (1) was calculated using distance restraints determined from 1H NMR spectroscopy. Eight of the lowest energy conformations from this study were used to identify non-peptide cores that mimic the spatial arrangement of the critical tripeptide region, dPhe-Arg-Trp, found in 1. From these studies, compound 2a, containing the cis-cyclohexyl core, was identified as a functional agonist of the melanocortin-4 receptor (MC4R) with an IC50 and EC50 below 10 nM.
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MC4R Agonists: Structural Overview on Antiobesity Therapeutics
2018, Trends in Pharmacological SciencesCitation Excerpt :In this study, the authors increased agonist’s potency by introducing triazoles and tetrazoles (Figure 5, Structures 1 and 2) [108]. Another very potent non-peptidic structure was reported one year later by Fotsch and co-workers [109], where low-energy structures from NMR data of HFRW were used to identify suitable ring structures. The most potent agonist was then designed, based on a cyclohexane 1,4-diamine decorated with tryptamine to mimic tryptophan, butyl guanidine to resemble arginine, and d-phenylalanine at the first position (Figure 5, Structure 3).
Classification study of novel piperazines as antagonists for the melanocortin-4 receptor based on least-squares support vector machines
2009, Chemometrics and Intelligent Laboratory SystemsStructure-activity relationships of novel piperazines as antagonists for the melanocortin-4 receptor
2007, Bioorganic and Medicinal Chemistry3 Recent Progress Toward Nonpeptide Ligands for the Melanocortin-4 Receptor
2007, Progress in Medicinal ChemistryCitation Excerpt :Efforts have been made to directly mimic the pharmacophore of the HFRW motif of melanocortin peptides in order to address the metabolic liability of peptides. [84] The cyclohexane (34) has been designed and synthesized by Fotsch et al. based on the solution structure of the cyclic peptide Ac-Nle-cyclo[Asp-Pro-dPhe-Arg-Trp-Lys]-NH2 determined by NMR [85]. Compound (34) is a potent and selective MC4R agonist (IC50=7.7 nM, EC50=4 nM, IA=93%).
Design, synthesis, and biological evaluation of a new class of small molecule peptide mimetics targeting the melanocortin receptors
2006, Bioorganic and Medicinal Chemistry LettersPrivileged structure based ligands for melanocortin-4 receptors-Aliphatic piperazine derivatives
2006, Bioorganic and Medicinal Chemistry Letters
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