title: Discovery, stereospecific characterization and peripheral modification of 1-(pyrrolidin-1-ylmethyl)-2-[(6-chloro-3-oxo-indan)-formyl]-1,2,3,4-tetrahydroisoquinolines as novel selective κ opioid receptor agonists.
abstract: A novel series of 1-(pyrrolidin-1-ylmethyl)-2-[(3-oxo-indan)-formyl]-1,2,3,4-tetrahydroisoquinoline derivatives maj-3a-maj-3u were synthesized and evaluated in vitro for their binding affinity at κ-opioid receptors. Maj-3c displayed the highest affinity for κ-opioid receptors (Ki = 0.033 nM) among all the compounds evaluated. Furthermore, all four stereoisomers of compound 3c were prepared, and (1S,18S)-3c was identified as the most potent (Ki = 0.0059 nM) κ-opioid receptor agonist among the four stereoisomers. Maj-3c produced significant antinociception (ED50 = 0.000406 mg kg(-1)) compared to U-50,488H and original BRL 52580 in the acetic acid writhing assay, but its strong sedative effect (ED50 = 0.000568 mg kg(-1)) observed in the mouse rotation test reduced its druggability. To minimize the central nervous system side effects, a series of hydroxyl-containing analogs of maj-3c were synthesized, and maj-11a was found to be a potent κ-opioid receptor agonist (Ki = 35.13 nM). More importantly, the dose for the sedative effect (ED50 = 9.29 mg kg(-1)) of maj-11a was significantly higher than its analgesic dose (ED50 = 0.392 mg kg(-1)), which made it a promising peripheral analgesic candidate compound with weak sedative side effects.
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China. xu_yungen@hotmail.com.
authors.forename: Zong-Jie
authors.initials: ZJ
authors.lastname: Gan
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Wang
authors.forename: Yun-Gen
authors.initials: YG
authors.lastname: Xu
authors.forename: Ting
authors.initials: T
authors.lastname: Guo
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Qiao
authors.initials: Q
authors.lastname: Song
authors.forename: Xue-Jun
authors.initials: XJ
authors.lastname: Xu
authors.forename: Shi-Yuan
authors.initials: SY
authors.lastname: Hu
authors.forename: Yu-Jun
authors.initials: YJ
authors.lastname: Wang
authors.forename: De-Chuan
authors.initials: DC
authors.lastname: Wang
authors.forename: De-Zhu
authors.initials: DZ
authors.lastname: Sun
authors.forename: Di
authors.initials: D
authors.lastname: Zhang
authors.forename: Tao
authors.initials: T
authors.lastname: Xi
authors.forename: Hao-Dong
authors.initials: HD
authors.lastname: Li
authors.forename: Hai-Bo
authors.initials: HB
authors.lastname: Zhang
authors.forename: Tai-Jun
authors.initials: TJ
authors.lastname: Hang
authors.forename: Hong-Guo
authors.initials: HG
authors.lastname: Lu
authors.forename: Jing-Gen
authors.initials: JG
authors.lastname: Liu
mesh_terms: D019342:Acetic Acid / Q000378:metabolism; D000700:Analgesics / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D055808:Drug Discovery; D007189:Indans / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D010147:Pain Measurement; D017933:Peripheral Nervous System / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D013237:Stereoisomerism; D044005:Tetrahydroisoquinolines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D014018:Tissue Distribution
chemical_list: C000605114:1-(pyrrolidin-1-ylmethyl)-2-((6-chloro-3-oxoindan)formyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline; D000700:Analgesics; D007189:Indans; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D044005:Tetrahydroisoquinolines; D019342:Acetic Acid