Reversal of subtype-selectivity and function by the introduction of a para-benzamidyl substituent to N-cyclopropylmethyl nornepenthone

Kong, Linghui; Ning, Kuan; Xiao, Lan; Lu, Jinjian; Chen, Baiyu; Ye, Rongrong; Li, Zixiang; Jiang, Shuang; Tang, Siyuan; Chai, Jing-Rui; Fang, Yun; Lan, Yong; Mai, Xiaobo; Xie, Qiong; Liu, Jinggen; Shao, Liming; Fu, Wei; Wang, Yujun; Li, Wei

doi:10.1016/j.ejmech.2023.115589

Cited by 1 publication

(2 citation statements)

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“…The binding pose of nalfurafine was extracted from its crystal structure in complex with the KOR (PDB entry, 7YIT). All compounds were subjected to energy minimization and refinement, following the methodologies outlined in previous studies . These compounds were then docked to the MOR and KOR structures, employing the docking parameters and procedures established earlier. , The validated complexes were plotted using the PyMOL (The PyMOL molecular graphics system, version 0.98, DeLano Scientific, Palo Alto, CA) software.…”

Section: Methodsmentioning

confidence: 99%

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Discovery of an Ortho-Substituted N-Cyclopropylmethyl-7α-phenyl-6,14-endoethano-tetrahydronorthebaine Derivative as a Selective and Potent Kappa Opioid Receptor Agonist with Subsided Sedative Effect

Li,

Ye,

et al. 2024

J. Med. Chem.

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Research into kappa opioid receptor (KOR) agonists with attenuated central-nervous-system side effects is a critical focus for developing productive and safe analgesics. Herein, a series of ortho-substituted N-cyclopropylmethyl-7α-phenyl-6,14endoethano-tetrahydronorthebaines were designed, synthesized, and subjected to bioassays. Compound 7a exhibited high subtype selectivity and potent agonistic activity toward KOR (KOR, K i = 3.9 nM, MOR/KOR = 270, DOR/KOR = 1075; [ 35 S]GTPγS binding, EC 50 = 3.4 nM). Additionally, this compound exhibited robust and persistent antinociceptive effects in rodent models with different animal strains (hot plate test, ED 50 = 0.20−0.30 mg/kg, i.p.; abdominal constriction test, ED 50 = 0.20−0.60 mg/kg, i.p.), with its KOR-mediated mechanism for antinociception firmly established. Notably, compound 7a, unlike conventional KOR agonists, displayed minimal sedation and aversion at the antinociceptive ED 50 dose. This feature addresses a crucial limitation in existing KOR agonists, positioning compound 7a as a promising novel therapeutic agent.

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Section: Methodsmentioning

confidence: 99%

“…62 These compounds were then docked to the MOR and KOR structures, employing the docking parameters and procedures established earlier. 37,62 The validated complexes were plotted using the PyMOL (The PyMOL molecular graphics system, version 0.98, DeLano Scientific, Palo Alto, CA) software.…”

Section: ■ Associated Contentmentioning

confidence: 99%