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1,2,3-Triazole Rings as a Disulfide Bond Mimetic in Chimeric AGRP-Melanocortin Peptides: Design, Synthesis, and Functional Characterization
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2017-12-19 00:00:00 , DOI: 10.1021/acschemneuro.7b00422 Srinivasa R. Tala 1 , Anamika Singh 1 , Cody J. Lensing 1 , Sathya M. Schnell 1 , Katie T. Freeman 1 , James R. Rocca 2 , Carrie Haskell-Luevano 1
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2017-12-19 00:00:00 , DOI: 10.1021/acschemneuro.7b00422 Srinivasa R. Tala 1 , Anamika Singh 1 , Cody J. Lensing 1 , Sathya M. Schnell 1 , Katie T. Freeman 1 , James R. Rocca 2 , Carrie Haskell-Luevano 1
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The melanocortin system is involved in the regulation of complex physiological functions, including energy and weight homeostasis, feeding behavior, inflammation, sexual function, pigmentation, and exocrine gland function. The five melanocortin receptors that belong to the superfamily of G protein-coupled receptors (GPCRs) are regulated by endogenously expressed agonists and antagonists. The aim of this study was to explore the potential of replacing the disulfide bridge in chimeric AGRP-melanocortin peptide Tyr-c[Cys-His-d-Phe-Arg-Trp-Asn-Ala-Phe-Cys]-Tyr-NH2 (1) with 1,2,3-triazole moieties. A series of 1,2,3-triazole-bridged peptidomimetics were designed, synthesized, and pharmacologically evaluated at the mouse melanocortin receptors. The ligands possessed nanomolar to micromolar agonist cAMP signaling potency. A key finding was that the disulfide bond in peptide 1 can be replaced with the monotriazole ring with minimal effect on the functional activity at the melanocortin receptors. The 1,5-disubstituted triazole-bridged peptide 6 showed equipotent functional activity at the mMC3R and modest 5-fold decreased agonist potency at the mMC4R compared to those of 1. Interestingly, the 1,4- and 1,5-disubstituted isomers of the triazole ring resulted in different selectivities at the receptor subtypes, indicating subtle structural features that may be exploited in the generation of selective melanocortin ligands. Introducing cyclic and acyclic bis-triazole moieties into chimeric AGRP template 1 generally decreased agonist activity. These results will be useful for the further design of neuronal chemical probes for the melanocortin receptors as well as in other receptor systems.
中文翻译：
1,2,3-三唑环作为嵌合AGRP-黑皮质素肽中的二硫键模拟物：设计，合成和功能表征
黑皮质素系统参与复杂的生理功能的调节，包括能量和体重的动态平衡，进食行为，炎症，性功能，色素沉着和外分泌腺功能。属于G蛋白偶联受体（GPCR）超家族的五个黑皮质素受体由内源性表达的激动剂和拮抗剂调节。这项研究的目的是探讨取代嵌合AGRP-黑皮质素肽Tyr-c [Cys-His- d -Phe-Arg-Trp-Asn-Ala-Phe-Cys] -Tyr-NH 2的潜力。（1）具有1,2,3-三唑部分。设计，合成了一系列1,2,3-三唑桥连的拟肽，并对小鼠黑皮质素受体进行了药理学评估。配体具有纳摩尔至微摩尔的激动剂cAMP信号传导能力。一个关键发现是肽1中的二硫键可以被单三唑环取代，而对黑皮质素受体的功能活性影响最小。所述1,5-二取代的三唑桥连的肽6表明等效的功能活性在mMC3R和适度的5倍的mMC4R相比，这些的降低激动剂效力1。有趣的是，三唑环的1，4-和1，5-二取代异构体在受体亚型上具有不同的选择性，表明在选择性黑皮质素配体的产生中可以利用微妙的结构特征。将环状和无环的双三唑部分引入嵌合AGRP模板1中通常会降低激动剂活性。这些结果对于进一步设计用于黑皮质素受体以及在其他受体系统中的神经元化学探针将是有用的。
更新日期：2017-12-19
中文翻译：
1,2,3-三唑环作为嵌合AGRP-黑皮质素肽中的二硫键模拟物：设计，合成和功能表征
黑皮质素系统参与复杂的生理功能的调节，包括能量和体重的动态平衡，进食行为，炎症，性功能，色素沉着和外分泌腺功能。属于G蛋白偶联受体（GPCR）超家族的五个黑皮质素受体由内源性表达的激动剂和拮抗剂调节。这项研究的目的是探讨取代嵌合AGRP-黑皮质素肽Tyr-c [Cys-His- d -Phe-Arg-Trp-Asn-Ala-Phe-Cys] -Tyr-NH 2的潜力。（1）具有1,2,3-三唑部分。设计，合成了一系列1,2,3-三唑桥连的拟肽，并对小鼠黑皮质素受体进行了药理学评估。配体具有纳摩尔至微摩尔的激动剂cAMP信号传导能力。一个关键发现是肽1中的二硫键可以被单三唑环取代，而对黑皮质素受体的功能活性影响最小。所述1,5-二取代的三唑桥连的肽6表明等效的功能活性在mMC3R和适度的5倍的mMC4R相比，这些的降低激动剂效力1。有趣的是，三唑环的1，4-和1，5-二取代异构体在受体亚型上具有不同的选择性，表明在选择性黑皮质素配体的产生中可以利用微妙的结构特征。将环状和无环的双三唑部分引入嵌合AGRP模板1中通常会降低激动剂活性。这些结果对于进一步设计用于黑皮质素受体以及在其他受体系统中的神经元化学探针将是有用的。
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