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首页> 外文期刊>Journal of Medicinal Chemistry >Development of Cyclic gamma-MSH Analogues with Selective hMC3R Agonist and hMC3R/hMC5R Antagonist Activities
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Development of Cyclic gamma-MSH Analogues with Selective hMC3R Agonist and hMC3R/hMC5R Antagonist Activities

机译：具有选择性hMC3R激动剂和hMC3R / hMC5R拮抗剂活性的环状gamma-MSH类似物的开发

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A series of cyclic lactam analogues of gamma-MSH (H-Tyr~1-Val~2-Met~3-Gly~4-His~5-Phe~6-Arg~7-Trp~8-Asp~9-Arg_(10)-Phe~(11)-Gly~(12)-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]-NH_2,was found to be a very potent and selective hMC3R agonist (EC_(50)=1.2 nM,112% act).In addition,analogue 13,c[Nle-Val-D-Nal(2')-Arg-Trp-Glu]-NH_2,was identified as an hMC3R/hMC5R antagonist with the best selectivity against the hMC4R in this series (pA_2(hMC3R)=8.4;pA_2(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.
机译：γ-MSH的一系列环状内酰胺类似物（H-Tyr〜1-Val〜2-Met〜3-Gly〜4-His〜5-Phe〜6-Arg〜7-Trp〜8-Asp〜9-Arg_ （10）-Phe〜（11）-Gly〜（12）-OH）具有紧靠药效团的大量疏水残基（Xaa-D-Phe / D-Nal（2'）-Arg-Trp）。通过固相法设计和合成。第5位引入了多种具有广泛疏水/亲水特性的氨基酸，以进一步探索它们在受体选择性中的互补作用。这些肽的生物学评估显示了几种具有有效hMC3R激动剂的类似物和hMC3R / hMC5R拮抗剂活性，以及​​良好的受体选择性。类似物4，c [Nle-Arg-D-Phe-Arg-Trp-Glu] -NH_2，是一种非常有效的选择性hMC3R激动剂（EC_（50） ＝ 1.2nM，112％作用）。另外，类似物13，c [Nle-Val-D-Nal（2'）-Arg-Trp-Glu] -NH_2被鉴定为具有最佳选择性的hMC3R / hMC5R拮抗剂。针对此系列中的hMC4R（pA_2（hMC3R）= 8.4; pA_2（hMC5R）= 8.7）。这些结果表明黑素皮质素受体选择性中的空间因素，并建议在紧邻黑素皮质素药效团的附近引入庞大的残基是设计新型hMC3R和hMC5R选择性配体的有效方法。

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