Interaction of the nicotinic agonist (R,S)-3-pyridyl-1-methyl-2-(3-pyridyl)-azetidine (MPA) with nicotinic acetylcholine receptor subtypes expressed in cell lines and rat cortex.
The interaction of the nicotinic agonist (R,S)-3-pyridyl-1-methyl-2-(3-pyridyl)-azetidine (MPA) with different nicotinic acetylcholine receptor (nAChR) subtypes was studied in cell lines and rat cortex. MPA showed an affinity (Ki = 1.21 nM) which was higher than anatoxin-a > (-)-nicotine > (+)-[R]nornicotine > (-)-[S]nornicotine > and (+)-nicotine, but lower than cytisine (Ki = 0.46 nM) in competing for (-)-[3H]nicotine binding in M10 cells, which stably express the recombinant alpha4beta2 nAChR subtype. A one-binding site model was observed in all competing experiments between (-)-[3H]nicotine binding and each of the agonists studied in M10 cells. MPA showed a 13-fold higher affinity for (-)-[3H]nicotine binding sites compared to the [3H]epibatidine binding sites in rat cortical membranes. In human neuroblastoma SH-SY5Y cells, which predominantly express the alpha3 nAChR subunit mRNA, MPA displaced [3H]epibatidine binding from a single population of the binding sites with an affinity in the same nM range as that observed MPA in displacing [3H]epibatidine binding in rat cortical membranes. Chronic treatment of M10 cells with MPA significantly up-regulated the number of (-)-[3H]nicotine binding sites in a concentration dependent manner. Thus MPA appears to have higher affinity to alpha4-subunit containing receptor subtype than alpha3-subunit containing receptor subtype of nAChRs. Furthermore MPA binds to alpha4beta2 receptor subtype with higher affinity than (-)-nicotine and behaves, opposite to cytisine, as a fult agonist in up-regulating the number of nAChRs.
Department of Clinical Neuroscience and Family Medicine, Karolinska Institute, Huddinge University Hospital, Sweden.
X
X
Zhang
Z H
ZH
Gong
K J
KJ
Fasth
B
B
Långström
A
A
Nordberg
D000470:Alkaloids / Q000378:metabolism; D000818:Animals; D001384:Azetidines / Q000378:metabolism / Q000494:pharmacology*; D001392:Azocines; D001667:Binding, Competitive; D002460:Cell Line; D002540:Cerebral Cortex / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D051379:Mice; D018722:Nicotinic Agonists / Q000494:pharmacology*; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology*; D011807:Quinolizines; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism*; D015854:Up-Regulation; D000093843:Quinolizidine Alkaloids
D000470:Alkaloids; D001384:Azetidines; D001392:Azocines; D018722:Nicotinic Agonists; D011725:Pyridines; D011807:Quinolizines; D011978:Receptors, Nicotinic; C114402:3-pyridyl-1-methyl-2-(3-pyridyl)azetidine; C004712:cytisine; D000093843:Quinolizidine Alkaloids