Holladay M W, Wasicak J T, Lin N H, He Y, Ryther K B, Bannon A W, Buckley M J, Kim D J, Decker M W, Anderson D J, Campbell J E, Kuntzweiler T A, Donnelly-Roberts D L, Piattoni-Kaplan M, Briggs C A, Williams M, Arneric S P
Neurological and Urological Diseases Research D-47W, Abbott Laboratory, Abbott Park, Illinois 60064-3500, USA.
J Med Chem. 1998 Feb 12;41(4):407-12. doi: 10.1021/jm9706224.
New members of a previously reported series of 3-pyridyl ether compounds are disclosed as novel, potent analgesic agents acting through neuronal nicotinic acetylcholine receptors. Both (R)-2-chloro-5-(2-azetidinylmethoxy)pyridine (ABT-594, 5) and its S-enantiomer (4) show potent analgesic activity in the mouse hot-plate assay following either intraperitoneal (i.p.) or oral (p.o.) administration, as well as activity in the mouse abdominal constriction (writhing) assay, a model of persistent pain. Compared to the S-enantiomer and to the prototypical potent nicotinic analgesic agent (+/-)-epibatidine, 5 shows diminished activity in models of peripheral side effects. Structure-activity studies of analogues related to 4 and 5 suggest that the N-unsubstituted azetidine moiety and the 2-chloro substituent on the pyridine ring are important contributors to potent analgesic activity.
已报道的一系列3-吡啶基醚化合物的新成员被披露为通过神经元烟碱型乙酰胆碱受体起作用的新型强效镇痛剂。(R)-2-氯-5-(2-氮杂环丁烷基甲氧基)吡啶(ABT-594, 5)及其S-对映体(4)在腹腔注射(i.p.)或口服(p.o.)给药后，在小鼠热板试验中均显示出强效镇痛活性，以及在小鼠腹部收缩(扭体)试验中也有活性，该试验是一种持续性疼痛模型。与S-对映体和典型的强效烟碱型镇痛剂(±)-埃博霉素相比，5在外周副作用模型中的活性降低。与4和5相关类似物的构效关系研究表明，N-未取代的氮杂环丁烷部分和吡啶环上的2-氯取代基是强效镇痛活性的重要贡献因素。
