Abstract
2'-Fluoro-3-(substituted pyridine)epibatidine analogues 7a-e and 8a-e were synthesized, and their in vitro and in vivo nAChR properties were determined. 2'-Fluoro-3'-(4″-pyridinyl)deschloroepibatidine (7a) and 2'-fluoro-3'-(3″-pyridinyl)deschloroepibatidine (8a) were synthesized as bioisosteres of the 4'-nitrophenyl lead compounds 5a and 5g. Comparison of the in vitro nAChR properties of 7a and 8a to those of 5a and 5g showed that 7a and 8a had in vitro nAChR properties similar to those of 5a and 5g but both were more selective for the α4β2-nAChR relative to the α3β4- and α7-nAChRs than 5a and 5g. The in vivo nAChR properties in mice of 7a were similar to those of 5a. In contrast, 8a was an agonist in all four mouse acute tests, whereas 5g was active only in a spontaneous activity test. In addition, 5g was a nicotine antagonist in both the tail-flick and hot-plate tests, whereas 8a was an antagonist only in the tail-flick test.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Analgesics / chemical synthesis*
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Analgesics / chemistry
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Analgesics / pharmacology
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Animals
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Body Temperature / drug effects
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Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
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Bridged Bicyclo Compounds, Heterocyclic / chemistry
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology
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Contraindications
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Female
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Male
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Mice
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Nicotinic Agonists / chemical synthesis
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Nicotinic Agonists / chemistry
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Nicotinic Agonists / pharmacology
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Nicotinic Antagonists / chemical synthesis
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Nicotinic Antagonists / chemistry
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Nicotinic Antagonists / pharmacology
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Oocytes / drug effects
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Oocytes / physiology
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Pain / drug therapy
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Pain / physiopathology
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Patch-Clamp Techniques
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Pyridines / chemical synthesis*
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Pyridines / chemistry
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Pyridines / pharmacology
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Radioligand Assay
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Rats
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Rats, Sprague-Dawley
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Receptors, Nicotinic / metabolism*
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Structure-Activity Relationship
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Xenopus
Substances
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Analgesics
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Bridged Bicyclo Compounds, Heterocyclic
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Nicotinic Agonists
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Nicotinic Antagonists
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Pyridines
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Receptors, Nicotinic
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epibatidine