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：121

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

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1998年 / 41卷 / 04期

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

页码：407 / 412

页数：6

共 31 条

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