Discovery of a Highly Selective and Potent kappa Opioid Receptor Agonist from N-Cyclopropylmethyl-7 alpha-phenyl-6,14-endoethanotetrahydronorthebaines with Reduced Central Nervous System (CNS) Side Effects Navigated by the Message-Address Concept
Discovery of a Highly Selective and Potent kappa Opioid Receptor Agonist from N-Cyclopropylmethyl-7 alpha-phenyl-6,14-endoethanotetrahydronorthebaines with Reduced Central Nervous System (CNS) Side Effects Navigated by the Message-Address Concept
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从 N-环丙基甲基-7 α-苯基-6,14-内乙烷四氢去西巴因中发现一种高度选择性和有效的 kappa 阿片受体激动剂，通过消息地址概念来减少中枢神经系统 (CNS) 副作用
DOI：
10.1021/acs.jmedchem.9b00857
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发表时间：
2019
影响因子：
7.3
通讯作者：
Zheng Yili
中科院分区：
文献类型：
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作者：
Xiao Li;Wang Yujun;Zhang Mumei;Wu Weiwei;Kong Linghui;Ma Yan;Xu Xuejun;Liu Xiao;He Qian;Qian Yuanyuan;Sun Huijiao;Wu Haihao;Lin Cheng;Huang Huoming;Ye Rongrong;Jiang Shuang;Ye Ru-Feng;Yuan Congmin;Fang Shengyang;Xue Dengqi;Yang Xicheng;Chen Hao;Zheng Yili
有效和安全的止痛药代表着急慢性疼痛治疗的医疗需求尚未得到满足。我们设计、合成了一系列ofN-cyclopropylmethyl-7α-phenyl-6，14-endoethanotetrahydronorthebaines，并对其进行了检测，发现了一种高选择性、高活性的κ阿片激动剂(κ，Ki=0.47nM，κ/μ=682，κ/δ=283)，并通过体外和体内抗伤害性实验证实了其活性。这种活体效应可被选择性κ拮抗剂Nor-BNI阻断。此外，与U50,488H相比，该化合物在其止痛剂量下没有诱导镇静，这是κ阿片受体激动剂的常见剂量限制效应。在SLL-039中发现的镇静/抗伤害作用的解离被认为与其苯甲酰胺基序在涉及V1182.63、W124EL1和E209EL2的一个独特的亚位点上的占据有关。
Effective and safe analgesics represent an unmet medical need for the treatment of acute and chronic pain. A series ofN-cyclopropylmethyl-7α-phenyl-6,14-endoethanotetrahydronorthebaines were designed, synthesized, and assayed, leading to the discovery of a benzylamine derivative (compound4, SLL-039) as a highly selective and potent κ opioid agonist (κ,Ki= 0.47 nM, κ/μ = 682, κ/δ = 283), which was confirmed by functional assaysin vitroand antinociceptive assaysin vivo. Thein vivoeffect could be blocked by pretreatment with the selective κ antagonist nor-BNI. Moreover, this compound did not induce sedation, a common dose limiting effect of κ opioid receptor agonists, at its analgesic dose compared to U50,488H. The dissociation of sedation/antinociception found in SLL-039 was assumed to be correlated with the occupation of its benzamide motif in a unique subsite involving V1182.63, W124EL1, and E209EL2.