Kappa (κ) opioid receptor selective antagonists are useful pharmacological tools in studying κ opioid receptors and have potential to be used as therapeutic agents for the treatment of a variety of diseases including mood disorders and drug addiction. Arodyn (Ac[Phe^1–3,Arg⁴,d-Ala⁸]Dyn A-(1–11)NH₂) is a linear acetylated dynorphin A (Dyn A) analog that is a potent and selective κ opioid receptor antagonist (Bennett et al. J Med Chem 2002;45:5617–5619) and prevents stress-induced reinstatement of cocaine-seeking behavior following central administration (Carey et al. Eur J Pharmacol 2007;569:84–89). To restrict its conformational mobility, explore possible bioactive conformations and potentially increase its metabolic stability we synthesized cyclic arodyn analogs on solid phase utilizing a novel ring-closing metathesis (RCM) reaction involving allyl-protected Tyr (Tyr(All)) residues. This approach preserves the aromatic functionality and directly constrains the side chains of one or more of the Phe residues. The novel cyclic arodyn analog 4 cyclized between Tyr(All) residues incorporated in positions 2 and 3 exhibited potent κ opioid receptor antagonism in the [³⁵S]GTPγS assay (K_B = 3.2 nM) similar to arodyn. Analog 3 cyclized between Tyr(All) residues in positions 1 and 2 also exhibited nanomolar κ opioid receptor antagonist potency (K_B = 27.5 nM) in this assay. These are the first opioid peptides cyclized via RCM involving aromatic residues, and given their promising pharmacological activity represent novel lead peptides for further exploration.

Kappa（κ）阿片受体选择性拮抗剂是研究κ阿片受体的有用药理工具，具有用作治疗包括情绪障碍和药物成瘾在内的多种疾病的潜力。Arodyn（Ac [Phe ^1–3，Arg ⁴，d -Ala ⁸ ] Dyn A-（1–11）NH ₂）是一种线性乙酰化强啡肽A（Dyn A）类似物，是一种有效且选择性的κ阿片受体拮抗剂（ Bennett等人，J Med Chem 2002； 45：5617–5619），并防止在中央给药后应激诱导的可卡因寻觅行为的恢复（Carey等人，Eur J Pharmacol2007; 569：84–89）。为了限制其构象流动性，探索可能的生物活性构象，并可能增加其代谢稳定性，我们利用涉及烯丙基保护的Tyr（Tyr（All））残基的新型开环复分解（RCM）反应，在固相上合成了环状芦丁类似物。该方法保留了芳族官能度并直接约束一个或多个Phe残基的侧链。在[ ³⁵ S]GTPγS分析（K _B  = 3.2 nM）中，与arodyn相似，在第2位和第3位掺入的Tyr（All）残基之间循环的新型环状arodyn类似物4表现出有效的κ阿片受体拮抗作用（K _B = 3.2 nM）。模拟3在此位置，在1和2位的Tyr（All）残基之间环化的环也显示出纳摩尔κ阿片受体拮抗剂的效价（K _B  = 27.5 nM）。这些是第一个通过RCM环化的涉及芳香族残基的阿片样肽，并且鉴于其有希望的药理活性，它们代表了进一步研究的新型先导肽。