Identification and initial structure-activity relationships of (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594), a potent, orally active, non-opiate analgesic agent acting via neuronal nicotinic acetylcholine receptors

被引:122
作者
Holladay, MW [1 ]
Wasicak, JT [1 ]
Lin, NH [1 ]
He, Y [1 ]
Ryther, KB [1 ]
Bannon, AW [1 ]
Buckley, MJ [1 ]
Kim, DJB [1 ]
Decker, MW [1 ]
Anderson, DJ [1 ]
Campbell, JE [1 ]
Kuntzweiler, TA [1 ]
Donnelly-Roberts, DL [1 ]
Piattoni-Kaplan, M [1 ]
Briggs, CA [1 ]
Williams, M [1 ]
Arneric, SP [1 ]
机构
[1] Abbott Labs, Neurol & Urol Dis Res D47W, Abbott Pk, IL 60064 USA
关键词
D O I
10.1021/jm9706224
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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 (ip) or oral (po) 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.
引用
收藏
页码:407 / 412
页数:6
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