Abstract：
The effective management of moderate to severe pain often relies on the use of analgesic agents. However, the widespread utility of these medications is hindered by the occurrence of several undesirable side effects. In light of this challenge, there is growing interest in the development of κ opioid receptor (KOR) agonists, which have shown promise in mitigating these adverse effects. In this study, leveraging the structural scaffold of compound D (our previous study), we embarked on the design, synthesis, and evaluation of a series of N\'-benzyl-3-chloro-N- ((1S,3R,4R)-3-((dimethylamino)methyl)-4-hydroxy-4-(3-methoxyphenyl)cyclohexyl)benzenesulfonamide derivatives. These compounds were subjected to comprehensive in vitro and in vivo test. Through systematic structure-activity relationship (SAR) exploration, we successfully identified compound 23p (Ki(KOR):1.9 nM) as a highly selective KOR ligand of new chemotype. 23p showed high clearance in vitro PK test, and abdominal contraction test showed potent antinociceptive effect. 23p and its O-demethyl metabolite 25 were both found in the plasma of mouse, 25 also showed potent affinity toward KOR (Ki(KOR): 3.1 nM), both they contribute to the analgesic effect. Moreover, 23p exhibited potent antinociceptive activity in abdominal constriction test, which was effectively abolished by pre-treatment of nor-BNI, a selective KOR antagonist.
摘要：
中度至重度疼痛的有效管理通常依赖于镇痛剂的使用。然而,这些药物的广泛使用受到一些不良副作用的阻碍。鉴于这一挑战，人们对κ阿片受体（KOR）激动剂的开发越来越感兴趣，在减轻这些不利影响方面表现出了希望。在这项研究中,利用化合物D的结构支架(我们之前的研究)，我们开始了设计，合成，和一系列N'-苄基-3-氯-N-（（1S，3R,4R)-3-((二甲基氨基)甲基)-4-羟基-4-(3-甲氧基苯基)环己基)苯磺酰胺衍生物。对这些化合物进行全面的体外和体内测试。通过系统的结构-活动关系(SAR)探索,我们成功鉴定化合物23p(Ki(KOR):1.9nM)为新化学型的高选择性KOR配体。23p在体外PK试验中显示出高清除率，腹部收缩试验显示出有效的抗伤害作用。23p及其O-去甲基代谢物25均在小鼠血浆中发现，25还显示出对KOR的有效亲和力（Ki（KOR）：3.1nM），它们都有助于镇痛作用。此外，23p在腹部收缩试验中表现出有效的抗伤害感受活性，通过nor-BNI的预处理有效废除了，选择性KOR拮抗剂。
