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

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.

Novel and Potent 6-Chloro-3-pyridinyl Ligands for the α4β2 Neuronal Nicotinic Acetylcholine Receptor

“…17 Modifications of Heterocyclic Amine and Trialkylammonium Moieties of 6-Chloro-3-pyridinylScheme 1. Synthesis of 6-Chloro-3-pyridinylmethyl Ligands with Modifications in the Heterocyclic Imine Moiety (1)(2)(3)(4)(5)(6)(7)(8)(9)(10) or Related Compounds (11)(12)(13)(14) methyl Ligands 18-23 (Scheme 2). The azetidine derivative 18 was prepared by coupling CCMP to 3-chloropropylamine in the usual manner, followed by cyclization in refluxing acetonitrile.…”

Neuronal nicotinic receptors as analgesic targets: It's a winding road

“…Similar to the anitinociceptive effects of nicotine and epibatidine, ABT-594-induced antinociception is also blocked by mecamylamine [19,20]. Furthermore, ABT-594 does not perturb the cardiovascular system, particularly when compared to epibatidine [22], and does not cause signs of physical dependence in mice. Thus, the preclinical data supported the view that ABT-594 could be a promising therapeutic drug for chronic pain patients.…”

QSAR study of a large set of 3-pyridyl ethers as ligands of the α4β2 nicotinic acetylcholine receptor

“…One hundred and fifty-eight diverse pyridyl ether analogues were taken from several published works [10][11][12][13][38][39][40][41][42][43][44]. Our study was based on two fundamental Fig.…”