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Design and Biological Evaluation of Selective Melanocortin Drugs
Author(s) -
McLeod Kaitlyn,
Soto Robert,
Cai Minying,
Hruby Victor
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.728.42
Subject(s) - melanocortin , g protein coupled receptor , receptor , melanocortin 4 receptor , hek 293 cells , chemistry , melanocortin receptor , melanocortin 3 receptor , cyclic adenosine monophosphate , pharmacology , biochemistry , biology
G‐protein coupled receptors (GPCRs), a large family of transmembrane proteins, are popular drug targets due to their signaling diversity and abundance in mammalian tissues. The melanocortin system is comprised of 5 GPCRs: hMC1R, hMC2R, hMC3R, hMC4R, and hMC5R. When stimulated by their endogenous ligand, α‐melanocortin stimulating hormone (α‐MSH), the melanocortin receptors induce an increase in the intracellular concentration of cyclic adenosine monophosphate (cAMP), resulting in cellular events that contribute to a diverse set of physiological phenomena including inflammation, sexual function, feeding behavior, and skin pigmentation. The tetrapeptide sequence, His‐D‐Phe‐Arg‐Trp, of α‐MSH is vital for ligand binding and activation of hMC1R, hMC3R, hMC4R, and hMC5R. In an effort to increase the selectivity and biostability of α‐MSH analogues, cyclization has been employed to conformationally constrain these peptides. A set of α‐MSH analogues have been evaluated for biological activity using HEK293 cells stably transfected with hMC1R, hMC3R, hMC4R, or hMC5R. Whole‐cell competitive radioligand binding assays were used to calculate IC50 values. Adenylate cyclase activity assays were used to calculate EC50 values for these drugs. We have shown that conformationally constraining peptides leads to receptor specificity, which is important for the future development of these peptides as pharmaceuticals. Selective agonists and antagonists for these receptors may benefit people suffering from diseases including diabetes, anorexia, obesity, and melanoma.