While the melanocortin receptors (MCRs) are known to be involved in numerous biological pathways, the potential roles of the MC5R have not been clearly elucidated in humans. Agouti-related protein (AgRP), an MC3R/MC4R antagonist and MC4R inverse agonist, contains an exposed β-hairpin loop composed of six residues (Arg-Phe-Phe-Asn-Ala-Phe) that is imperative for binding and function. Within this active loop of AgRP, four human missense polymorphisms were deposited into the NIH Variation Viewer database. These polymorphisms, Arg111Cys, Arg111His, Phe112Tyr, and Ala115Val (AgRP full-length numbering), were incorporated into the peptide macrocycles c[Pro1-Arg2-Phe3-Phe4-Xaa5-Ala6-Phe7-dPro8], where Xaa was Dap5 or Asn5, to explore the functional effects of these naturally occurring substitutions in a simplified AgRP scaffold. All peptides lowered potency at least 10-fold in a cAMP accumulation assay compared to the parent sequences at the MC4Rs. Compounds MDE 6-82-3c, ZMK 2-82, MDE 6-82-1c, ZMK 2-85, and ZMK 2-112 are also the first AgRP-based chemotypes that antagonize the MC5R.

中文翻译：

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Agouti相关蛋白（AgRP）人类单核苷酸多态性（SNP）在AgRP衍生的大环支架c [Pro-Arg-Phe-Phe-Asn-Ala-Phe-dPro]中的结合降低了Melanocortin-4受体拮抗剂的效力和结果在发现黑皮质素5受体拮抗剂中。

尽管已知黑皮质素受体（MCRs）参与许多生物学途径，但尚未明确阐明MC5R在人类中的潜在作用。刺痛相关蛋白（AgRP）是一种MC3R / MC4R拮抗剂和MC4R反向激动剂，包含一个暴露的β-发夹环，该环由六个残基（Arg-Phe-Phe-Asn-Ala-Phe）组成，这些残基对于结合和功能必不可少。在这个活跃的AgRP循环中，四个人类错义多态性被存入NIH Variation Viewer数据库。这些多态性Arg111Cys，Arg111His，Phe112Tyr和Ala115Val（AgRP全长编号）被整合到肽大环c [Pro1-Arg2-Phe3-Phe4-Xaa5-Ala6-Phe7-dPro8]中，其中Xaa是Dap5或Asn5。 ，以探索在简化的AgRP支架中这些天然取代基的功能效果。与MC4Rs的亲本序列相比，所有肽在cAMP累积分析中的效价降低至少10倍。化合物MDE 6-82-3c，ZMK 2-82，MDE 6-82-1c，ZMK 2-85和ZMK 2-112也是拮抗MC5R的首批基于AgRP的化学型。