• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Journal of Medicinal Chemistry >Structure-Activity Relationships of γ-MSH Analogues at the Human Melanocortin MC3, MC4, and MC5 Receptors. Discovery of Highly Selective hMC3R, hMC4R, and hMC5R Analogues
【24h】

Structure-Activity Relationships of γ-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受体上的结构活性关系。发现高度选择性的hMC3R，hMC4R和hMC5R类似物

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

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 α-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 γ-MSH, two different series of γ-MSH analogues have been designed and synthesized and their biological activities determined a 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 γ-MSH around the highly conserved sequence can led 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 γ-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：广泛的研究表明，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，并且在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γ-MSH中的受体活性构象，已设计并合成了两个不同系列的γ-MSH类似物，它们的生物学活性决定了hMC3R，hMC4R和hMC5R。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含Gly〜4）的] -Arg-Phe-Gly-NH_2对于选择性更重要。第二个系列是由D-2-萘基丙氨酸（D-Nal（2'））对γ-MSH序列在位置6和8进行扫描，然后用Pro（类似物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，类似物15 H-Tyr-Val-Nle-Gly-Aib-Phe-Arg-D-Nal（2'）-Asp-Arg-Phe-Gly-NH_2是hMC5R的高度选择性和强效激动剂。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，它是hMC4R的强效激动剂，并且可以进一步评估该类似物的喂养行为和脂肪储存的调节。

著录项

相似文献

  • 外文文献
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号