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

M W Holladay; 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

doi:10.1021/jm9706224

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.

Authors

M W Holladay¹, 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

Affiliation

¹ Neurological and Urological Diseases Research D-47W, Abbott Laboratory, Abbott Park, Illinois 60064-3500, USA. mark.w.holladay@abbott.com

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.

MeSH terms

Administration, Oral
Analgesics, Non-Narcotic / administration & dosage
Analgesics, Non-Narcotic / chemistry
Analgesics, Non-Narcotic / pharmacology*
Animals
Azetidines / administration & dosage
Azetidines / chemistry
Azetidines / pharmacology*
Diastole / drug effects
Female
Humans
Injections, Intraperitoneal
Kinetics
Mice
Molecular Structure
Muscle Contraction / drug effects
Neuroblastoma
Neurons / drug effects
Neurons / physiology*
Nicotinic Agonists / administration & dosage
Nicotinic Agonists / chemistry
Nicotinic Agonists / pharmacology*
Oocytes / physiology
Pain Measurement
Pain*
Pyridines / administration & dosage
Pyridines / chemistry
Pyridines / pharmacology*
Rats
Receptors, Nicotinic / drug effects
Receptors, Nicotinic / metabolism
Receptors, Nicotinic / physiology*
Recombinant Proteins / drug effects
Recombinant Proteins / metabolism
Stereoisomerism
Structure-Activity Relationship
Tumor Cells, Cultured
Xenopus

Substances

5-(2-azetidinylmethoxy)-2-chloropyridine
Analgesics, Non-Narcotic
Azetidines
Nicotinic Agonists
Pyridines
Receptors, Nicotinic
Recombinant Proteins