Selectivity of coronaridine congeners at nicotinic acetylcholine receptors and inhibitory activity on mouse medial habenula

The inhibitory activity of coronaridine congeners on human (h) alpha 4 beta 2 and alpha 7 nicotinic acetylcholine receptors (AChRs) is determined by Ca2+ influx assays, whereas their effects on neurons in the ventral inferior (VI) aspect of the mouse medial habenula (MHb) are determined by patch-clamp recordings. The Ca2+ influx results clearly establish that coronaridine congeners inhibit ha alpha 3 beta 4 AChRs with higher selectivity compared to h alpha 4 beta 2 and h alpha 7 subtypes, and with the following potency sequence, for h alpha 4 beta 2: (+/-)-18-methoxycoronaridine [(+/-)-18-MC] > (+)-catharanthine > (+/-)-18-methylaminocoronaridine [(+/-)-18-MAC] similar to (+/-)-18-hydroxycoronaridine [(+/-)-18-HC]; and for h alpha 7: (+)-catharanthine > (+/-)-18-MC > (+/-)-18-HC > (+/-)-18-MAC. Interestingly, the inhibitory potency of (+)-catharanthine (27 +/- 4 mu M) and (+/-)-18-MC (28 +/- 6 mu M) on MHb (VI) neurons was lower than that observed on h alpha 3 beta 4 AChRs, suggesting that these compounds inhibit a variety of endogenous alpha 3 beta 4* AChRs. In addition, the interaction of bupropion with (-)-ibogaine sites on h alpha 3 beta 4 AChRs is tested by [H-3]ibogaine competition binding experiments. The results indicate that bupropion binds to ibogaine sites at desensitized h alpha 3 beta 4 AChRs with 2-fold higher affinity than at resting receptors, suggesting that these compounds share the same binding sites. In conclusion, coronaridine congeners inhibit h alpha 3 beta 4 AChRs with higher selectivity compared to other AChRs, by interacting with the bupropion (luminal) site. Coronaridine congeners also inhibit alpha 3 beta 4*AChRs expressed in MHb (VI) neurons, supporting the notion that these receptors are important endogenous targets for their anti-addictive activities.