2. Academic Validation
  3. 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

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

  • J Med Chem. 1998 Feb 12;41(4):407-12. doi: 10.1021/jm9706224.
M W Holladay 1,  J T Wasicak,  N H Lin,  Y He,  K B Ryther,  A W Bannon,  M J Buckley,  D J Kim,  M W Decker,  D J Anderson,  J E Campbell,  T A Kuntzweiler,  D L Donnelly-Roberts,  M Piattoni-Kaplan,  C A Briggs,  M Williams,  S P Arneric
Affiliations

Affiliation

  • 1 Neurological and Urological Diseases Research D-47W, Abbott Laboratory, Abbott Park, Illinois 60064-3500, USA. [email protected]
PMID: 9484491 DOI: 10.1021/jm9706224
Abstract

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.

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