title: The Pharmacological Heterogeneity of Nepenthone Analogs in Conferring Highly Selective and Potent κ-Opioid Agonistic Activities.
abstract: To develop novel analgesics with no side effects or less side effects than traditional opioids is highly demanded to treat opioid receptor mediated pain and addiction issues. Recently, κ-opioid receptor (KOR) has been established as an attractive target, although its selective agonists could bear heterogeneous pharmacological activities. In this study, we designed and synthesized two new series of nepenthone derivatives by inserting a spacer (carbonyl) between 6α,14α-endo-ethenylthebaine and the 7α-phenyl substitution of the skeleton and by substituting the 17-N-methyl group with a cyclopropylmethyl group. We performed in vitro tests (binding and functional assays) and molecular docking operations on our newly designed compounds. The results of wet-experimental measures and modeled binding structures demonstrate that these new compounds are selective KOR agonists with nanomolar level affinities. Compound 4 from these new derivatives showed the highest affinity (Ki= 0.4 ± 0.1 nM) and the highest selectivity (μ/κ = 339, δ/κ = 2034) toward KOR. The in vivo tests revealed that compound 4 is able to induce stronger (ED50= 2.1 mg/kg) and much longer antinociceptive effect than that of the typical KOR agonist U50488H (ED50= 4.4 mg/kg). Therefore, compound 4 can be used as a perfect lead compound for future design of potent analgesics acting through KOR.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University , Shanghai 201203, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Collaborative Innovation Center for Brain Science , Shanghai 201203, China.
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Long
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University , Shanghai 201203, China.
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Qian
authors.affiliation: Department of Pharmacy, Dalian Medical University , Dalian 116044, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Long
authors.affiliation: Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Collaborative Innovation Center for Brain Science , Shanghai 201203, China.
authors.forename: Xue-Jun
authors.initials: XJ
authors.lastname: Xu
authors.affiliation: Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Collaborative Innovation Center for Brain Science , Shanghai 201203, China.
authors.forename: Yu-Jun
authors.initials: YJ
authors.lastname: Wang
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University , Shanghai 201203, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Shen
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University , Shanghai 201203, China.
authors.forename: Zuo-Neng
authors.initials: ZN
authors.lastname: Wang
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University , Shanghai 201203, China.
authors.forename: Xi-Cheng
authors.initials: XC
authors.lastname: Yang
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University , Shanghai 201203, China.
authors.forename: Li
authors.initials: L
authors.lastname: Xiao
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University , Shanghai 201203, China.
authors.forename: Hong-Peng
authors.initials: HP
authors.lastname: Sun
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University , Shanghai 201203, China.
authors.forename: Yu-Long
authors.initials: YL
authors.lastname: Xu
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University , Shanghai 201203, China.
authors.forename: Yi-Yi
authors.initials: YY
authors.lastname: Chen
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University , Shanghai 201203, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Xie
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University , Shanghai 201203, China.
authors.forename: Yong-Hui
authors.initials: YH
authors.lastname: Wang
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University , Shanghai 201203, China.
authors.forename: Li-Ming
authors.initials: LM
authors.lastname: Shao
authors.affiliation: Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Collaborative Innovation Center for Brain Science , Shanghai 201203, China.
authors.forename: Jing-Gen
authors.initials: JG
authors.lastname: Liu
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University , Shanghai 201203, China.
authors.forename: Zhui-Bai
authors.initials: ZB
authors.lastname: Qiu
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University , Shanghai 201203, China.
authors.forename: Wei
authors.identifier: 0000-0002-2335-8908
authors.initials: W
authors.lastname: Fu
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D006801:Humans; D062105:Molecular Docking Simulation; D009019:Morphinans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D020836:Protein Structure, Quaternary; D051381:Rats; D017473:Receptors, Opioid, kappa / Q000819:agonists; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D000701:Analgesics, Opioid; D009019:Morphinans; D017473:Receptors, Opioid, kappa; C105912:nepenthone
keywords: 4,5-epoxymorphinans; binding structure; nepenthones; pharmacological heterogeneity; structure−activity relationship; κ-opioid receptor; μ-opioid receptor