Synthesis and nicotinic activity of epiboxidine: an isoxazole analogue of epibatidine.
Synthetic (+/-)-epiboxidine (exo-2-(3-methyl-5-isoxazolyl)-7-azabicyclo[2.2.1]heptane) is a methylisoxazole analog of the alkaloid epibatidine, itself a potent nicotinic receptor agonist with antinociceptive activity. Epiboxidine contains a methylisoxazolyl ring replacing the chloropyridinyl ring of epibatidine. Thus, it is also an analog of another nicotinic receptor agonist, ABT 418 ((S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole), in which the pyridinyl ring of nicotine has been replaced by the methylisoxazolyl ring. Epiboxidine was about 10-fold less potent than epibatidine and about 17-fold more potent than ABT 418 in inhibiting [3H]nicotine binding to alpha 4 beta 2 nicotinic receptors in rat cerebral cortical membranes. In cultured cells with functional ion flux assays, epiboxidine was nearly equipotent to epibatidine and 200-fold more potent than ABT 418 at alpha 3 beta 4(5) nicotinic receptors in PC12 cells. Epiboxidine was about 5-fold less potent than epibatidine and about 30-fold more potent than ABT 418 in TE671 cells with alpha 1 beta 1 gamma delta nicotinic receptors. In a hot-plate antinociceptive assay with mice, epiboxidine was about 10-fold less potent than epibatidine. However, epiboxidine was also much less toxic than epibatidine in mice.
Badio
B
B
Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Garraffo
H M
HM
Plummer
C V
CV
Padgett
W L
WL
Daly
J W
JW
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000648:ultrastructure; D005724:Ganglia / Q000187:drug effects / Q000648:ultrastructure; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D051379:Mice; D009538:Nicotine / Q000378:metabolism / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D009619:Nociceptors / Q000187:drug effects; D016716:PC12 Cells; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects; D014316:Tritium
D014151:Anti-Anxiety Agents; D007555:Isoxazoles; D018722:Nicotinic Agonists; D011759:Pyrrolidines; D011978:Receptors, Nicotinic; C106388:epiboxidine; D014316:Tritium; C088383:3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole; D009538:Nicotine