The dynorphin (Dyn) A analog arodyn (Ac[Phe^1-3,Arg⁴,d-Ala⁸]Dyn A-(1–11)NH₂) is a κ opioid receptor-selective antagonist, but as a linear peptide it is conformationally flexible and subject to metabolism by proteases. To restrict its conformational flexibility both short- and long-range cyclizations via ring-closing metathesis (RCM) involving residues in both the N-terminal “message” and C-terminal “address” sequences were explored. Cyclization between allyglycine (AllGly) residues in positions 5 and 8 yielded peptides with the highest κ opioid receptor affinity (K_i = 54 and 63 nM) and selectivity for κ over µ receptors (185- and 149-fold) comparable to arodyn (175-fold), with similar results for the peptides with the cis and trans double bond configurations; both isomers exhibited competitive antagonism of κ opioid receptors with potencies similar to arodyn. The minor cis isomer cyclized between AllGly residues in positions 2 and 8 exhibited similar κ receptor affinity to arodyn, but lacked selectivity for κ over µ opioid receptors. These results provide important structure-activity relationship information for cyclization of arodyn that we are using in the design of the next generation of cyclic arodyn analogs.

强啡肽 (Dyn) A 类似物 Arodyn (Ac[Phe ^1-3 ,Arg ⁴ , d -Ala ⁸ ]Dyn A-(1–11)NH ₂ ) 是一种 κ 阿片受体选择性拮抗剂，但作为一种线性肽，它构象灵活，易被蛋白酶代谢。为了限制其构象灵活性，研究了通过闭环复分解 (RCM) 进行的短程和长程环化，涉及 N 端“信息”和 C 端“地址”序列中的残基。位置 5 和 8 中的甘氨酸 (AllGly) 残基之间的环化产生了具有最高 κ 阿片受体亲和力 ( K _i = 54 和 63 nM）和对 μ 受体的 κ 选择性（185 倍和 149 倍）与 arodyn 相当（175 倍），对于具有顺式和反式双键构型的肽具有相似的结果；两种异构体均表现出对 κ 阿片受体的竞争性拮抗作用，其效力与 Arodyn 相似。在位置 2 和 8 的 AllGly 残基之间环化的次要顺式异构体表现出与 Arodyn 相似的 κ 受体亲和力，但缺乏对 μ 阿片受体的 κ 选择性。这些结果为我们用于设计下一代环状 Arodyn 类似物的 Arodyn 环化提供了重要的构效关系信息。