Discovery of N'-benzyl-3-chloro-N-((1S,3R,4R)-3-((dimethylamino)methyl)-4-hydroxy-4-(3-methoxyphenyl)cyclohexyl)benzenesulfonamide as a novel selective KOR ligand

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 (K_i(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 (K_i(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.

Agonists; Pain; κ opioid receptor (KOR).