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 (-)-[H-3]nicotine binding in M10 cells, which stably express the recombinant alpha(2)beta(2) 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 (-)-[H-3]nicotine binding sites compared to the [H-3]epibatidine binding sites in rat cortical membranes. In human neuroblastoma SH-SY5Y cells, which predominantly express the alpha(3) nAChR subunit mRNA, MPA displaced [H-3]epibatidine binding from a single population of the binding sites with an affinity in the same nhl range as that observed MPA in displacing [H-3]epibatidine binding in rat cortical membranes. Chronic treatment of M10 cells with MPA significantly up-regulated the number of (-)-[H-3]nicotine binding sites in a concentration dependent manner. Thus MPA appears to have higher affinity to alpha 4-subunit containing receptor subtype than alpha 3(-)subunit containing receptor subtype of nAChRs. Furthermore MPA binds to alpha(4)beta(2) receptor subtype with higher affinity than (-)-nicotine and behaves, opposite to cytisine, as a full agonist in up-regulating the number of nAChRs. (C) 1998 Elsevier Science Ltd. All rights reserved.