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J Med Chem. 2007 Dec 13;50(25):6383-91. Epub 2007 Nov 10.

Synthesis and nicotinic acetylcholine receptor binding properties of bridged and fused ring analogues of epibatidine.

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Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, North Carolina 27709, USA.


Epibatidine analogues 3- 5, possessing the pyridine ring fused to the 2,3 position of the 7-azabicyclo[2.2.1]heptane ring, and analogue 8a, possessing a benzene ring fused to the 5,6 position, were synthesized by procedures involving key steps of trapping 2,3-pyridyne, 3,4-pyridyne, and benzyne with tert-butyl 1 H-pyrrole-1-carboxylate. Two epibatidine analogues, 6 and 7, which have the 2'-chloropyridine ring bridged to the 7-azabicyclo[2.2.1]heptane ring via a methylene group, were synthesized, where the key step was an intramolecular reductive palladium-catalyzed Heck-type coupling. Even though the conformationally restricted epibatidine analogues, 3- 7, and the benzo analogue 8a possess nAChR pharmacophore features thought to be needed for alpha(4)beta(2) binding, they all showed low affinity for nAChRs relative to epibatidine. These studies provide new information concerning the pharmacophore for nAChRs and suggest that nitrogen lone-pair directionality and steric factors may be important. Interestingly, N-methylepibatidine, prepared as a standard compound for the study of bridged analogues 6 and 7, was a potent nAChR mixed agonist antagonist.

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