Mayorov Alexander V, Cai Minying, Chandler Kevin B, Petrov Ravil R, Van Scoy April R, Yu Zerui, Tanaka Dustin K, Trivedi Dev, Hruby Victor J
Department of Chemistry, University of Arizona, Tucson, Arizona 85721, USA.
J Med Chem. 2006 Mar 23;49(6):1946-52. doi: 10.1021/jm0510326.
A series of cyclic lactam analogues of gamma-MSH (H-Tyr1-Val2-Met3-Gly4-His5-Phe6-Arg7-Trp8-Asp9-Arg10-Phe11-Gly12-OH) with a bulky hydrophobic residue in the direct proximity to the pharmacophore (Xaa-D-Phe/D-Nal(2')-Arg-Trp) were designed and synthesized by solid-phase methods. A variety of amino acids with a broad range of hydrophobic/hydrophilic properties was introduced in position 5 to further explore their complementary role in receptor selectivity. Biological evaluation of these peptides revealed several analogues with potent hMC3R agonist and hMC3R/hMC5R antagonist activities, and good receptor selectivity. Analogue 4, c[Nle-Arg-D-Phe-Arg-Trp-Glu]-NH2, was found to be a very potent and selective hMC3R agonist (EC50=1.2 nM, 112% act). In addition, analogue 13, c[Nle-Val-D-Nal(2')-Arg-Trp-Glu]-NH2, was identified as an hMC3R/hMC5R antagonist with the best selectivity against the hMC4R in this series (pA2(hMC3R)=8.4; pA2(hMC5R)=8.7). These results indicate the significance of steric factors in melanocortin receptor selectivity and suggest that introduction of bulky residues in the direct proximity to the melanocortin pharmacophore is an effective approach to design of novel hMC3R and hMC5R selective ligands.
设计并通过固相方法合成了一系列γ-MSH（H-Tyr1-Val2-Met3-Gly4-His5-Phe6-Arg7-Trp8-Asp9-Arg10-Phe11-Gly12-OH）的环状内酰胺类似物，这些类似物在紧邻药效团（Xaa-D-Phe/D-Nal(2')-Arg-Trp）的位置带有一个庞大的疏水残基。在第5位引入了具有广泛疏水/亲水性质的多种氨基酸，以进一步探索它们在受体选择性中的互补作用。对这些肽的生物学评估揭示了几种具有强效hMC3R激动剂和hMC3R/hMC5R拮抗剂活性以及良好受体选择性的类似物。发现类似物4，c[Nle-Arg-D-Phe-Arg-Trp-Glu]-NH2，是一种非常强效且选择性的hMC3R激动剂（EC50 = 1.2 nM，活性为112%）。此外，类似物13，c[Nle-Val-D-Nal(2')-Arg-Trp-Glu]-NH2，被鉴定为一种hMC3R/hMC5R拮抗剂，在该系列中对hMC4R具有最佳选择性（pA2(hMC3R)=8.4；pA2(hMC5R)=8.7）。这些结果表明空间因素在黑皮质素受体选择性中的重要性，并表明在紧邻黑皮质素药效团的位置引入庞大残基是设计新型hMC3R和hMC
