Arias, HR, Jin, Xiaotao, Feuerbach, Dominik and Drenan, RM (2017) Nicotinic acetylcholine receptor selectivity and inhibitory activity on mouse medial habenula by coronaridine congeners. international journal of biochemistry and cell biology, 92. pp. 202-209.

Abstract

The inhibitory activity of coronaridine congeners on human (h) α4β2 and α7 nicotinic acetylcholine receptors (AChRs) is determined by Ca2+ influx assays, whereas their effects on mouse medial habenula (MHb) neurons is determined by patch-clamp recordings. The Ca2+ influx results clearly establish that coronaridine congeners inhibit hα3β4 AChRs with higher selectivity compared to hα4β2 and hα7 subtypes, and with the following potency sequence, for hα4β2: (±)-18-methoxycoronaridine [(±)-18-MC] > (+)-catharanthine > (±)-18-methylaminocoronaridine [(±)-18-MAC] ~ (±)-18-hydroxycoronaridine [(±)-18-HC]; and for hα7: (+)-catharanthine > (±)-18-MC > (±)-18-HC > (±)-18-MAC. Interestingly, the inhibitory potency of (+)-catharanthine (27 ± 4 µM) and (±)-18-MC (28 ± 6 µM) on MHb neurons was lower than that observed on hα3β4 AChRs, suggesting that these compounds inhibit a variety of endogenous α3β4* AChRs. In addition, the interaction of bupropion with (-)-ibogaine sites on hα3β4 AChRs is tested by [3H]ibogaine competition binding experiments. The results indicate that bupropion binds to ibogaine sites at desensitized hα3β4 AChRs with 2-fold higher affinity than resting receptors, suggesting that these compounds share the same binding sites. In conclusion, coronaridine congeners inhibit hα3β4 AChRs with comparatively higher selectivity compared to other AChRs, by interacting with the bupropion (luminal) site. These compounds also inhibit α3β4*AChRs expressed in MHb neurons, supporting the notion that these receptors are important endogenous targets for their anti-addictive activities.

Item Type:	Article
Date Deposited:	04 Nov 2017 00:45
Last Modified:	04 Nov 2017 00:45
URI:	https://oak.novartis.com/id/eprint/33944