Discovery of Novel Potent and Selective Agonists at the Melanocortin-3 Receptor

Carotenuto, Alfonso; Merlino, Francesco; Cai, Minying; Brancaccio, Diego; Yousif, Ali Munaim; Novellino, Ettore; Hruby, Victor J.; Grieco, Paolo

doi:10.1021/acs.jmedchem.5b01285

Cited by 21 publications

(54 citation statements)

References 37 publications

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“…Two selective agonists have been reported for the hMC3R (Table 1): a partial agonist at the hMC3R was selective over the hMC4R [119] and one compound has been reported selective for the hMC3R over the hMC1R and hMC4R [127]. At the mMC3R (Table 2), one compound has also shown to be selective for the mMC3R over the mMC1R [47].…”

Section: Selective Compoundsmentioning

confidence: 99%

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Bench-top to clinical therapies: A review of melanocortin ligands from 1954 to 2016

Ericson

Lensing

Fleming

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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The discovery of the endogenous melanocortin agonists in the 1950s have resulted in sixty years of melanocortin ligand research. Early efforts involved truncations or select modifications of the naturally occurring agonists leading to the development of many potent and selective ligands. With the identification and cloning of the five known melanocortin receptors, many ligands were improved upon through bench-top in vitro assays. Optimization of select properties resulted in ligands adopted as clinical candidates. A summary of every melanocortin ligand is outside the scope of this review. Instead, this review will focus on the following topics: classic melanocortin ligands, selective ligands, small molecule (non-peptide) ligands, ligands with sex-specific effects, bivalent and multivalent ligands, and ligands advanced to clinical trials. Each topic area will be summarized with current references to update the melanocortin field on recent progress.

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Section: Selective Compoundsmentioning

confidence: 99%

“…At the mMC3R (Table 2), one compound has also shown to be selective for the mMC3R over the mMC1R [47]. Of the MC3R selective compounds, two were derivatives of α-MSH [47, 119] and one based upon the MTII/SHU9119 template [127]. …”

Section: Selective Compoundsmentioning

confidence: 99%

Bench-top to clinical therapies: A review of melanocortin ligands from 1954 to 2016

Ericson

Lensing

Fleming

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…8 was also docked against an h MC3R model, 22 using the program AUTODOCK. 24 This gave a high populated low energy cluster for the 8 / h MC3R complex, whose best scored pose is shown in Figure 2.…”

Section: Resultsmentioning

confidence: 99%

“…22 The initial pose for the h MC3R/ 8 or h MC3R/ 1 complexes was generated by docking the lowest energy conformers of 8 and 1 obtained by NMR to the h MC3R model using the program AUTODOCK 4.0. 24 The side chains of His 6 , DPhe 7 , Arg 8 , and Trp 9 of 8 and 1 were considered flexible in the docking procedure.…”

Section: Methodsmentioning

confidence: 99%

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Development of Macrocyclic Peptidomimetics Containing Constrained α,α-Dialkylated Amino Acids with Potent and Selective Activity at Human Melanocortin Receptors

et al. 2018

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We report the development of macrocyclic melanocortin derivatives of MT-II and SHU-9119, achieved by modifying the cycle dimension and incorporating constrained amino acids in ring-closing. This study culminated in the discovery of novel agonists/antagonists with an unprecedented activity profile by adding pieces to the puzzle of the melanocortin receptor selectivity. Finally, the resulting 19- and 20-membered rings represent a suitable frame for the design of further therapeutic ligands as selective modulators of the melanocortin system.

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Molecular signatures of human melanocortin receptors for ligand binding and signaling

Yang

Harmon

2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Human melanocortin receptors (hMCRs) belong to the seven-transmembrane (TM) domain proteins. There are five hMCR subtypes and each of these receptor subtypes has different patterns of tissue expression and physiological function. The endogenous agonists for hMCRs are α-, β-, and γ-MSH and ACTH and endogenous antagonists are Agouti and AGRP which are the only known naturally occurring antagonists for the receptors. These peptides have their own profiles regarding the relative potency for specific hMCR subtype. Extensive studies have been performed to examine the molecular basis of the hMCRs for different ligand binding affinity and potency. Studies indicate that natural ligand α-MSH utilizes conserved amino acid residues for MCR specific binding (orthosteric binding) while synthetic ligands utilize non-conserved amino acid residues for receptor subtype specific binding (allosteric binding). ACTH is the only endogenous agonist for hMC2R and more amino acid residues at hMC2R are required for ACTH binding and signaling. HMCR computer modeling provides the detailed information of ligand and MCR interaction. This review provides the latest understanding of the molecular basis of the hMCRs for ligand binding and signaling. This article is part of a Special Issue entitled: Melanocortin Receptors - edited by Ya-Xiong Tao.

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Discovery of Novel Potent and Selective Agonists at the Melanocortin-3 Receptor

Cited by 21 publications

References 37 publications

Bench-top to clinical therapies: A review of melanocortin ligands from 1954 to 2016

Bench-top to clinical therapies: A review of melanocortin ligands from 1954 to 2016

Development of Macrocyclic Peptidomimetics Containing Constrained α,α-Dialkylated Amino Acids with Potent and Selective Activity at Human Melanocortin Receptors

Molecular signatures of human melanocortin receptors for ligand binding and signaling

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