Epibatidine and ABT 418 reveal selective losses of alpha 4 beta 2 nicotinic receptors in Alzheimer brains.
Subtypes of nicotinic acetylcholine receptors (nAChRs) were characterized in human temporal cortex and in a alpha 4 beta 2 nAChR-transfected M10 cell line using the nicotinic agonists epibatidine, ABT 418 and (-)nicotine in competition studies with [3H]nicotine and [3H]cytisine. The three agonists best fitted to an one-site model in M10 cells with the rank of potencies: epibatidine > > (-)-nicotine > ABT 418. Heterogeneous nAChRs were revealed for epibatidine and ABT 418 in the human temporal cortex. Both compounds labelled a major binding site (Ki 0.35 nM and 68.6 nM respectively) and an additional minor binding site with higher affinity (Ki 0.002 nM and 0.86 nM respectively). Corresponding data for (-)nicotine were a major site (Ki 2.80 nM) and an additional minor site with lower affinity (Ki 2150 nM). Selective losses in the major population of nAChR were observed in the temporal cortex of brains from individuals with Alzheimer's disease with all three agonists. This suggested that the alpha 4 beta 2 nAChR subunit might be the most vulnerable in Alzheimer's disease (AD) and a possible target for therapeutic strategies.
Warpman
U
U
Department of Clinical Neuroscience and Family Medicine, Huddinge University Hospital, Sweden.
Nordberg
A
A
D000368:Aged; D000369:Aged, 80 and over; D000470:Alkaloids / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001392:Azocines; D001667:Binding, Competitive / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002478:Cells, Cultured; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology*; D007700:Kinetics; D051379:Mice; D009538:Nicotine / Q000378:metabolism; D018722:Nicotinic Agonists / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D011807:Quinolizines; D011978:Receptors, Nicotinic / Q000145:classification / Q000378:metabolism*; D013702:Temporal Lobe / Q000187:drug effects / Q000378:metabolism*; D014162:Transfection; D000093843:Quinolizidine Alkaloids
D000470:Alkaloids; D014151:Anti-Anxiety Agents; D001392:Azocines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007555:Isoxazoles; D009538:Nicotine; D018722:Nicotinic Agonists; D011725:Pyridines; D011759:Pyrrolidines; D011807:Quinolizines; D011978:Receptors, Nicotinic; C088383:3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole; C004712:cytisine; D000093843:Quinolizidine Alkaloids; C082748:epibatidine