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
Synthesis and nicotinic acetylcholine receptor binding properties of bridged and fused ring analogues of epibatidine
Carroll, F., Robinson, TP., Brieaddy, L., Atkinson, R., Mascarella, S., Damaj, MI., Martin, BR., & Navarro, H. (2007). Synthesis and nicotinic acetylcholine receptor binding properties of bridged and fused ring analogues of epibatidine. Journal of Medicinal Chemistry, 50(25), 6383-6391.
Abstract
Publications Info
To contact an RTI author, request a report, or for additional information about publications by our experts, send us your request.
Meet the Experts
View All ExpertsRecent Publications
Article
Multifaceted risk for non-suicidal self-injury only versus suicide attempt in a population-based cohort of adults
Article
Long-term effects of a diet supplement containing Cannabis sativa oil and Boswellia serrata in dogs with osteoarthritis following physiotherapy treatments
Article
The influence of mediators on the relationship between antenatal opioid agonist exposure and the severity of neonatal opioid withdrawal syndrome
Article