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  • Title: 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.
    Author: Holladay MW, Wasicak JT, Lin NH, He Y, Ryther KB, Bannon AW, Buckley MJ, Kim DJ, Decker MW, Anderson DJ, Campbell JE, Kuntzweiler TA, Donnelly-Roberts DL, Piattoni-Kaplan M, Briggs CA, Williams M, Arneric SP.
    Journal: J Med Chem; 1998 Feb 12; 41(4):407-12. PubMed ID: 9484491.
    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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