Editorial [Hot Topic: Melanocortin Receptor Ligands and Their Potential Therapeutic Uses (Guest Editor: Ning Xi)]

Melanocortin receptors (MCRs) belong to the superfamily of 7-transmembrane G-protein coupled receptors (GPCRs). Five MCR subtypes, named MC1-5 receptors, have been identified and cloned to date. The identification of hypothalamic melanocortin receptors, MC3R and MC4R, as central components of feeding behavior and metabolism have helped build a picture, albeit incomplete, of the neuronal pathways involved in energy homeostasis. Thus, the intervention of neural MCR pathway may be a viable way to treat metabolic disorders such as obesity. Neural MCRs also participate in the regulation of sexual function, thus providing an alternative, centrally mediated therapeutic approach for erectile and other sexual dysfunctions. To this end, MC3/4R agonists and antagonists based on peptide, peptidomimetic, and small molecule structures have been prepared and evaluated for their biological activities. This, in turn, has enhanced our understandings on the physiological functions of the central melanocortin system. This special issue of “Current Topic in Medicinal Chemistry” is organized to highlight recent advances in the field of melanocortins. Six articles from researchers involved in the investigation of MCR ligands and their potential therapeutic uses are included. Hongmao Sun and David Fry start the issue with an in-depth review on the molecular modeling of melanocortin receptors. The understanding of how a MCR ligand interacts with each MCR subtype is essential to design potent, selective MCR ligands. In their article, Sun and Fry describe three molecular modeling approaches for MCRs, i.e., structure-based, ligand-based methods and proteochemometrics. The strengths and limitations of these approaches are evaluated. The authors conclude that the determination of the high resolution X-ray crystal structure of bovine rhodopsin (a GPCR with structure closely related to MCR), the availability of many selective MC4R agonists and the mature proteochemometrics all provide better than ever useful information to assist the design of potent and selective MCR ligands. The next three articles are focused on the design and synthesis of potent, selective MC3R and MC4R ligands. First, Liang Zeng Yan, Hansen M. Hsiung, Mark L. Heiman, Robert A. Gadski, Paul J. Emmerson, JeAnne Hertel, David Flora, Patrick Edwards, Dave Smiley, Lianshan Zhang, Saba Husain, Steven D. Kahl, Richard D. DiMarchi, and John P. Mayer from Eli Lily present their work on MC4R agonists based on the native β-MSH(5-22) sequence. Optimization efforts led them to identify a novel series of disulfide constrained hexapeptides that showed improved potency in binding MC4R and enhanced selectivity over MC1R. These cyclic peptides also demonstrated in vivo efficacy in reducing food intake in animal feeding models. The next article describes the recent development of small molecule-based MC4R agonists and antagonists. During the discussion of small molecule MC4R agonists, Feroze Ujjainwalla and Iyassu K. Sebhat divide the subject into two portions: rational peptidomimetic design which includes privileged structure approach, as well as cyclization and molecular modeling approaches; and hit to lead discovery of MC4R agonists. Their insightful structural analysis of MC4R ligands will benefit anyone who is interested in this field. In the following review, Professor Victor J. Hruby, Minying Cai, James P. Cain, Alexander V. Mayorov, Matthew M. Dedek and Devendra Trivedi discuss the biological functions attributed to the MC3R, and summarize the efforts to design and synthesize ligands that are potent and selective for the MC3R. Various linear and cyclic peptide templates based on α-, β-, and γ-MSH, as well as several peptidomimetic and small molecule design approaches leading to potent and selective hMC3R agonists and antagonists are provided.........