title: Synthesis and biological evaluation at nicotinic acetylcholine receptors of N-arylalkyl- and N-aryl-7-azabicyclo[2.2.1]heptanes.
abstract: A new series of N-arylalkyl-substituted 7-azabicyclo[2.2.1]heptanes and N-aryl-substituted 7-azabicyclo[2.2.1]heptanes were synthesized and evaluated as potential ligands for neuronal nicotinic acetylcholine receptors. The in vitro binding affinities (K(i)) of the 7-azabicyclo[2.2.1]heptane derivatives were measured by inhibition of [(3)H]cytisine binding to rat brain tissue. The most potent ligand of the series was found to be N-(3-pyridylmethyl)-7-azabicyclo[2.2.1]heptane (5b, K(i) = 98 nM). The chloro analogue (5a, K(i) = 245 nM) 5a and epibatidine (1) produced dose-dependent analgesia in both hotplate and tail-flick tests when administered subcutaneously. However, when compounds 1 and 5a,b were administered intrathecally, all produced analgesia in the tail-flick test but only 5a produced analgesia in the hotplate test.
authors.affiliation: Department of Chemistry, University of New Orleans, New Orleans, LA 70148, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Cheng
authors.forename: Chunming
authors.initials: C
authors.lastname: Zhang
authors.forename: Edwin D
authors.initials: ED
authors.lastname: Stevens
authors.forename: Sari
authors.initials: S
authors.lastname: Izenwasser
authors.forename: Dean
authors.initials: D
authors.lastname: Wade
authors.forename: Shaoyi
authors.initials: S
authors.lastname: Chen
authors.forename: Dennis
authors.initials: D
authors.lastname: Paul
authors.forename: Mark L
authors.initials: ML
authors.lastname: Trudell
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004298:Dopamine / Q000378:metabolism; D066298:In Vitro Techniques; D007278:Injections, Spinal; D008024:Ligands; D051379:Mice; D018722:Nicotinic Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010147:Pain Measurement; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D018712:Analgesics, Non-Narcotic; D019086:Bridged Bicyclo Compounds, Heterocyclic; D008024:Ligands; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; C082748:epibatidine; D004298:Dopamine