Selectivity of coronaridine congeners at nicotinic acetylcholine receptors and inhibitory activity on mouse medial habenula |
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| Institution: | 1. Department of Basic Sciences, California Northstate University College of Medicine, Elk Grove, CA, USA;2. Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA;3. Novartis Institutes for Biomedical Research, Basel, Switzerland;1. SRI Biosciences, a Division of SRI International, Menlo Park, CA, USA;2. University of California, San Francisco, CA, USA;3. James Madison University, Harrisonburg, VA, USA;1. Grating Technology Laboratory, Changchun Institute of Optics and Fine Mechanics and Physics, Chinese Academy of Sciences, Changchun, Jilin 130033, China;2. University of Chinese Academy of Sciences, Beijing 100049, China;3. NeuroSearch A/S, Pederstrupvej 93, 2750 Ballerup, Denmark;4. Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark;5. Faculty of Pharmacy, A15, The University of Sydney, New South Wales 2006, Australia;6. Aniona ApS, Baltorpvej 154, 2750 Ballerup, Denmark;1. Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8675, Japan;2. Molecular Chirality Research Center, Chiba University, 1-33, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan |
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| 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 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 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 (VI) 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 at resting receptors, suggesting that these compounds share the same binding sites. In conclusion, coronaridine congeners inhibit hα3β4 AChRs with higher selectivity compared to other AChRs, by interacting with the bupropion (luminal) site. Coronaridine congeners also inhibit α3β4*AChRs expressed in MHb (VI) neurons, supporting the notion that these receptors are important endogenous targets for their anti-addictive activities. |
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| Keywords: | Nicotinic acetylcholine receptor Coronaridine congeners 18-Methoxycoronaridine (+)-Catharanthine Medial habenula Brain slices |
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