Synthesis and biological evaluation at nicotinic acetylcholine receptors of N-arylalkyl- and N-aryl-7-azabicyclo[2.2.1]heptanes.
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.
Cheng
Jie
J
Department of Chemistry, University of New Orleans, New Orleans, LA 70148, USA.
Zhang
Chunming
C
Stevens
Edwin D
ED
Izenwasser
Sari
S
Wade
Dean
D
Chen
Shaoyi
S
Paul
Dennis
D
Trudell
Mark L
ML
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
D018712:Analgesics, Non-Narcotic; D019086:Bridged Bicyclo Compounds, Heterocyclic; D008024:Ligands; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; C082748:epibatidine; D004298:Dopamine