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首页> 外文期刊>Journal of Medicinal Chemistry >Structure-activity relationships of gamma-MSH analogues at the human melanocortin MC3, MC4, and MC5 receptors. discovery of highly selective hMC3R, hMC4R, and hMC5R analogues.
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Structure-activity relationships of gamma-MSH analogues at the human melanocortin MC3, MC4, and MC5 receptors. discovery of highly selective hMC3R, hMC4R, and hMC5R analogues.

机译：γ-MSH类似物在人类黑皮质素MC3，MC4和MC5受体上的构效关系。发现高度选择性的hMC3R，hMC4R和hMC5R类似物。

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It has been shown by extensive studies that melanotropin bioactivities are critically dependent on the core or central tetrapeptide sequence, His-Phe-Arg-Trp, and in alpha-MSH it has been demonstrated further that a reverse-turn type conformation exists at this pharmacophore. To probe the receptor active conformation of the pharmacophore His-Phe-Arg-Trp in gamma-MSH, two different series of gamma-MSH analogues have been designed and synthesized and their biological activities determined at hMC3R, hMC4R, and hMC5R. The 1st series consists of a cyclic scan using different disulfides or lactam bridges. It was found that cyclization of the native gamma-MSH around the highly conserved sequence can lead to shifts in affinity and selectivity for hMC4R instead of the hMC3R as seen in the native peptide. Furthermore, a 23-membered ring is desirable for potency (e.g., analogues 6 and 10) whereas a 26-membered ring (analogue 1, H-Tyr-Val-c[Cys-Gly-His-Phe-Arg-Trp-Cys]-Arg-Phe-Gly-NH(2) with Gly(4)) is more important for selectivity. The 2nd series is made of d-2-naphthylalanine (d-Nal(2')) scan of the gamma-MSH sequence at position 6 and 8 and the replacement of His(5) with Pro (analogue 13). Analogue 12, H-Tyr-Val-Nle-Gly-His-Phe-Arg-d-Nal(2')-Asp-Arg-Phe-Gly-NH(2), is a potent and selective antagonist at the hMC4R, and analogue 15, H-Tyr-Val-Nle-Gly-Aib-Phe-Arg-d-Nal(2')-Asp-Arg-Phe-Gly-NH(2), is a highly selective and potent agonist of the hMC5R. A most promising analogue is 13, H-Tyr-Val-Nle-Gly-Pro-d-Nal(2')-Arg-Trp-Asp-Arg-Phe-Gly-NH(2), which is a very potent agonist of the hMC4R, and this analogue can be further evaluated for feeding behavior and the regulation of fat stores.
机译：大量研究表明，黑素蛋白的生物活性主要取决于核心或中央四肽序列His-Phe-Arg-Trp，而在α-MSH中，进一步证明了该药效团存在反向型构象。 。为了探测药效基团His-Phe-Arg-Trp在gamma-MSH中的受体活性构象，已设计并合成了两个不同系列的gamma-MSH类似物，并在hMC3R，hMC4R和hMC5R上确定了它们的生物学活性。第一个系列包括使用不同的二硫键或内酰胺桥的循环扫描。发现在高度保守的序列周围的天然γ-MSH的环化可导致对hMC4R而不是如在天然肽中所见的hMC3R的亲和力和选择性的改变。此外，23元环对于效力是理想的（例如，类似物6和10），而26元环（类似物1，H-Tyr-Val-c [Cys-Gly-His-Phe-Arg-Trp-Cys ] -Arg-Phe-Gly-NH（2）与Gly（4））对于选择性而言更为重要。第二个系列是由d-2-萘基丙氨酸（d-Nal（2'））扫描位置6和8处的γ-MSH序列，以及用Pro（模拟物13）替代His（5）制成的。类似物12，H-Tyr-Val-Nle-Gly-His-Phe-Arg-d-Nal（2'）-Asp-Arg-Phe-Gly-NH（2），在hMC4R上是一种有效的选择性拮抗剂，和类似物15，H-Tyr-Val-Nle-Gly-Aib-Phe-Arg-d-Nal（2'）-Asp-Arg-Phe-Gly-NH（2），是高选择性和强效的激动剂hMC5R。最有前途的类似物是13，H-Tyr-Val-Nle-Gly-Pro-d-Nal（2'）-Arg-Trp-Asp-Arg-Phe-Gly-NH（2），是一种非常有效的激动剂可以进一步评估hMC4R的类似物，从而进一步评估其喂养行为和脂肪储存调节。

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