title: Design, synthesis and biological evaluation of aminobenzyloxyarylamide derivatives as selective κ opioid receptor antagonists.
abstract: Opioid receptors play an important role in both behavioral and mood functions. Based on the structural modification of LY2456302, a series of aminobenzyloxyarylamide derivatives were designed and synthesized as κ opioid receptor antagonists. The κ opioid receptor binding ability of these compounds were evaluated with opioid receptors binding assays. Compounds 1a-d showed high affinity for κ opioid receptor. Especially for compound 1c, exhibited a significant Kivalue of 15.7 nM for κ opioid receptor binding and a higher selectivity over μ and δ opioid receptors compared to (±)LY2456302. In addition, compound 1c also showed potent κ antagonist activity with κ IC50= 9.32 nM in [35S]GTP-γ-S functional assay. The potential use of the representative compounds as antidepressants was also investigated. The most potent compound 1c not only exhibited potent antidepressant activity in the mice forced swimming test, but also displayed the effect of anti-anxiety in the elevated plus-maze test.
authors.affiliation: Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Junwei
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Song
authors.affiliation: Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Anhua
authors.initials: A
authors.lastname: Xu
authors.affiliation: Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Bao
authors.affiliation: Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China. Electronic address: xyg@cpu.edu.cn.
authors.forename: Yungen
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China. Electronic address: zhuqihua@vip.126.com.
authors.forename: Qihua
authors.initials: Q
authors.lastname: Zhu
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D051379:Mice; D009292:Narcotic Antagonists / Q000138:chemical synthesis / Q000494:pharmacology; D011485:Protein Binding; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors*; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship
chemical_list: D000928:Antidepressive Agents; D001549:Benzamides; D009292:Narcotic Antagonists; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; C000590915:Aticaprant
keywords: Aminobenzyloxyarylamides; Antidepressants; LY2456302; Selectivity; κ opioid receptor antagonists