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

Abstract

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.

Melanocortins, Melanocortin Receptors and Multiple Sclerosis

“…In addition to melanocortins, the naturally occurring agonists of MCR, many pharmacologic agonists have been synthesized and tested for MCR subtype specificity, for longer half-lives than the rapidly degraded melanocortin peptides, and for reduction in steroidogenic or other side effects [ 4 , 11 , 35 ] (reviews). These include agents targeted to allosteric (extracellular), orthosteric (transmembrane, where ACTH and melanocortins bind) and signal transduction (intracellular) sites on MCR.…”

The constitutive activity of melanocortin‐4 receptors in cAMP pathway is allosterically modulated by zinc and copper ions

“…The important role of melanocortin‐4 receptors (MC 4 R) in energy homeostasis, sexual functions, neuroprotection, and neurogenesis (Wikberg and Mutulis, ; Tao, ) has made these G protein‐coupled receptors attractive drug targets in the central nervous system (CNS). Despite being very promising targets for several clinical trials, there is only a limited number of therapeutically approved drugs for MC 4 Rs (Ericson et al, ), mainly because the signal transduction of MC 4 Rs is subject to considerable complexity including conformational adjustments, oligomerization, and effects of different modulators (Biebermann et al, ; Kopanchuk et al, ; Müller, Berkmann, Scheerer, Biebermann, and Kleinau, ). There is increasing evidence that MC 4 R can form homo‐ and heterodimers or higher‐order oligomers (Elsner et al, ; Kopanchuk et al, ; Nickolls and Maki, ; Rediger et al, ; Chapman and Findlay, ) and the ligand binding within MC 4 R homodimers is governed by asymmetric regulation of co‐operative‐binding sites (Kopanchuk et al, , ).…”

Repository corticotropin injection as adjunctive therapy in patients with rheumatoid arthritis who have failed previous therapies with at least three different modes of action

“…Since melanocortins possess the ability to be pro-resolving molecules, they are attractive options for patients with inflammatory diseases. Synthetic melanocortins have been developed that are characterized by enhanced potency, improved duration of activity compared to endogenous melanocortins, and resistance to proteolytic activity 35. In addition, selective agonist peptides, selective antagonist peptides, and small-molecule ligands have been and are being developed in order to target particular melano-cortin receptors to exert control in particular pathologies; for example, MC 4 R has been the frequent target of development of agonists because of the association between this receptor and obesity 35…”