J Med Chem
Center for Organic and Medicinal Chemistry, Research Triangle Institute, P.O. Box 12194, Research Triangle Park, NC 27709, USA.
Published: July 2012
Herein, we report the synthesis and nicotinic acetylcholine receptor (nAChR) in vitro and in vivo pharmacological properties of 2'-fluoro-3'-(substituted phenyl)deschloroepibatidines 5b-g, analogues of 3'-(4-nitrophenyl) compound 5a. All compounds had high affinity for α4β2-nAChR and low affinity for α7-nAChR. Initial electrophysiological studies showed that all analogues were antagonists at α4β2-, α3β4-, and α7-nAChRs. The 4-carbamoylphenyl analogue 5g was highly selective for α4β2-nAChR over α3β4- and α7-nAChRs. All the analogues were antagonists of nicotine-induced antinociception in the tail-flick test. Molecular modeling docking studies using the agonist-bound form of the X-ray crystal structure of the acetylcholine binding protein suggested several different binding modes for epibatidine, varenicline, and 5a-g. In particular, a unique binding mode for 5g was suggested by these docking simulations. The high binding affinity, in vitro efficacy, and selectivity of 5g for α4β2-nAChR combined with its nAChR functional antagonist properties suggest that 5g will be a valuable pharmacological tool for studying the nAChR and may have potential as a pharmacotherapy for addiction and other central nervous system disorders.
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http://dx.doi.org/10.1021/jm300575y | DOI Listing |
J Physiol Sci
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Department of Autonomic Neuroscience, Tokyo Metropolitan Institute for Geriatrics and Gerontology, 35-2 Sakaecho, Itabashi-ku, 173-0015, Tokyo, Japan.
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School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
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Institute of Toxicology, College of Preventive Medicine, Army Medical University, Chongqing 400038, China.
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Department of Pharmaceutical Sciences, Medicinal Chemistry Section "Pietro Pratesi", University of Milan, Via L. Mangiagalli 25, Milan 20133, Italy.
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