The centrally expressed melanocortin-3 and -4 receptors (MC3R/MC4R) have been studied as possible targets for weight management therapies, with a preponderance of studies focusing on the MC4R. Herein, a novel tetrapeptide scaffold [Ac-Xaa¹-Arg-(pI)DPhe-Xaa⁴-NH₂] is reported. The scaffold was derived from results obtained from a MC3R mixture-based positional scanning campaign. From these results, a set of 48 tetrapeptides were designed and pharmacologically characterized at the mouse melanocortin-1, -3, -4, and -5 receptors. This resulted in the serendipitous discovery of nine compounds that were MC3R agonists (EC₅₀ < 1000 nM) and MC4R antagonists (5.7 < pA₂ < 7.8). The three most potent MC3R agonists, 18 [Ac-Arg-Arg-(pI)DPhe-Tic-NH₂], 1 [Ac-His-Arg-(pI)DPhe-Tic-NH₂], and 41 [Ac-Arg-Arg-(pI)DPhe-DNal(2′)-NH₂] were more potent (EC₅₀ < 73 nM) than the melanocortin tetrapeptide Ac-His-DPhe-Arg-Trp-NH₂. This template contains a sequentially reversed “Arg-(pI)DPhe” motif with respect to the classical “Phe-Arg” melanocortin signaling motif, which results in pharmacology that is first-in-class for the central melanocortin receptors.

中文翻译：

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发现基于序列Ac-Xaa ¹ -Arg-（pI）DPhe-Xaa ⁴ -NH ₂的混合药理学Melanocortin-3激动剂和Melanocortin-4受体四肽拮抗剂化合物（TACO）。

已经研究了集中表达的黑皮质素-3和-4受体（MC3R / MC4R）作为体重控制治疗的可能靶标，其中许多研究集中在MC4R上。在此，报道了新型的四肽支架[Ac-Xaa ¹ -Arg-（pI）DPhe-Xaa ⁴ -NH ₂ ]。支架是从基于MC3R混合物的位置扫描运动获得的结果中得出的。根据这些结果，设计了一组48种四肽，并在小鼠黑皮质素-1，-3，-4和-5受体上进行了药理学表征。这偶然发现了九种化合物，它们分别是MC3R激动剂（EC ₅₀ <1000 nM）和MC4R拮抗剂（5.7 <pA ₂ <7.8）。三种最有效的MC3R激动剂，18 [Ac-Arg-Arg-（pI）DPhe-Tic-NH ₂ ]，1 [Ac-His-Arg-（pI）DPhe-Tic-NH ₂ ]和41 [Ac-Arg-Arg-（pI） DPhe-DNal（2'）-NH ₂ ]比黑皮质素四肽Ac-His-DPhe-Arg-Trp-NH ₂更有力（EC ₅₀ <73 nM）。该模板包含相对于经典的“ Phe-Arg”黑皮质素信号转导基序顺序颠倒的“ Arg-（pI）DPhe”基序，其产生的药理学对于中枢黑皮质素受体是一流的。