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Structure-Activity Relationships of the Peptide Kappa Opioid Receptor Antagonist Zyklophin

机译：肽Kappa阿片受体拮抗剂Zyklophin的结构 - 活性关系

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Kappa opioid receptor (KOR) antagonists have recently demonstrated potential utility in the treatment of depression, anxiety, and cocaine addiction [1,2]. Non-peptide KOR selective antagonists, however, exhibit exceptionally long durations of action (weeks after a single dose) that may complicate and potentially limit their therapeutic application [3]. Our research group has designed KOR antagonists based on the endogenous KOR peptide dynorphin (Dyn) A. We have designed and synthesized the Dyn A(1-11) amide analog zyklophin, which is a KOR selective antagonist both in vitro [4] and in vivo [2]. It exhibits a finite duration of action (12-18h) and appears to cross the blood-brain barrier after systemic administration to antagonize KOR in the CNS [2]. Hence, we are exploring the structure-activity relationships of zyklophin in order to enhance its antagonist potency and examine its potential interactions with KOR. Several linear (1 and 2) and cyclic analogs of zyklophin were synthesized. The cyclic analogs included analogs with amino acid substitutions (e.g. 3 and 4), different N-alkyl groups and variations in the ring.
机译：Kappa阿片受体（Kor）拮抗剂最近在治疗抑郁症，焦虑和可卡因成瘾时表现出潜在的效用[1,2]。然而，非肽KOR选择性拮抗剂表现出具有复杂性和可能限制其治疗施用的异常长度的动作（单剂量后的数周）[3]。我们的研究小组已设计了基于KOR拮抗剂内源性肽KOR强啡肽（的Dyn）A.我们设计并合成了的Dyn A（1-11）酰胺类似物zyklophin，这是一个KOR选择性拮抗剂在体外[4]和在体内[2]。它表现出有限的作用持续时间（12-18h），似乎在系统施用后越过血脑屏障，以在CNS中拮抗kor [2]。因此，我们正在探索Zyklopham的结构 - 活性关系，以提高其拮抗剂效力，并检查其与Kor的潜在相互作用。合成了几种线性（1和2）和Zyklophin的环状类似物。环状类似物包括氨基酸取代（例如3和4）的类似物，不同的N-烷基和环的变化。

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