Introduction
MCL 0020 is a synthetic tripeptide with the structure of Ac-D-2Nal-Arg-2Nal-NH2 (2-Nal= 3-(2-naphthyl)-L-alanine; D-2-Nal = 3-(2-naphthyl)-D-alanine). It is discovered by Chaki et al. and shown to be a potent and selective melanocortin-4 (MC4) receptor antagonist. In comparison with the HFRW peptide, the His- moiety is deleted in MCL 0020 and the Trp-group is replaced by 2'-naphthy-alanine. The key Phe residue is substituted by 2' -naphthy-alanine for functional antagonism.
Biological Activity
MCL 0020 possesses high affinity for the MC4 receptor with an IC50 value of 11.6nM, and negligible affinities for the MC1 and MC3 receptors. The elimination of the imidazole of His-residue might be responsible for its selectivity over MC3R. MCL 0020 significantly attenuates the cAMP release induced by α-MSH in COS-1 cells expressing the MC4 receptor without affecting basal cAMP levels. The involvement of the MC4 receptor in stress and stress-related behavior is also investigated using MC4R agonists and this selective antagonist. In addition, MCL 0020 significantly prevents swim stress-induced reduction in the time spent in the light area in the mouse light/dark exploration test.
Function
To date, five types of receptor subtype for melanocortin (MC1-MC5) have been cloned. Among them, melanocortin MC3 mRNA has been found in distinct areas of the brain as well as placental and gut tissues, while melanocortin MC4 receptor has been found only in the brain. There are several lines of evidence suggesting a relationship between stress-related behavior and the brain melanocortinergic system. Moreover, melanocortins have been shown to exert anxiogenic-like behavior. The melanocortin MC4 receptor is of interest in terms of the central regulation of feeding behavior and energy expenditure. The melanocortin MC4 receptor antagonist, MCL 0020 shows anti-stress and anxiolytic-like activity in rodent models. Taken together, the brain melanocortinergic system may be involved in stress-related behaviors and disorders, and the melanocortin MC4 receptor may mediate these events. Moreover, melanocortin MC4 receptor antagonists may prove effective for the treatment of subjects with anxiety and anorectic disorders.
References:
1. Chaki, S., Ogawa, S. I., Toda, Y., Funakoshi, T., & Okuyama, S. (2003). Involvement of the melanocortin MC4 receptor in stress-related behavior in rodents. European journal of pharmacology, 474(1), 95-101.
