IDENTIFICATION AND INITIAL STRUCTURE-ACTIVITY-RELATIONSHIPS OF 5-(2-AZETIDINYLMETHOXY)-2-CHLOROPYRIDINE(ABT-594), A POTENT, ORALLY-ACTIVE, NONOPIATE ANALGESIC AGENT ACTING VIA NEURONAL NICOTINIC ACETYLCHOLINE-RECEPTORS

New members of a previously reported series of 3-pyridyl ether compoun ds are disclosed as novel, potent analgesic agents acting through neur onal nicotinic acetylcholine receptors. Both (R)-2-chloro-5-(2-azetidi nylmethoxy)pyridine (ABT-594, 5) and its S-enantiomer (4) show potent analgesic activity in the mouse hot-plate assay following either intra peritoneal (ip) or oral (po) administration, as well as activity in th e mouse abdominal constriction (writhing) assay, a model of persistent pain. Compared to the S-enantiomer and to the prototypical potent nic otinic analgesic agent (+/-)-epibatidine, 5 shows diminished activity in models of peripheral side effects. Structure-activity studies of an alogues 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.