Arias, Hugo R, Targowska-Duda, Katarzyna M, Feuerbach, Dominik and Jozwiak, Krzysztof (2015) Coronaridine congeners inhibit human α3β4 Nicotinic Acetylcholine Receptors by interacting with luminal and non-luminal sites. Biochemistry.

Abstract

To characterize the interaction of coronaridine congeners with human (h) α3β4 nicotinic acetylcholine receptors (AChRs), structural and functional approaches were used. The results established that coronaridine congeners inhibit (±)-epibatidine-induced Ca2+ influx in hα3β4 AChRs with the following potency (IC50’s in μM) sequence: (-)-ibogamine (0.62 ± 0.23) ~ (+)-catharanthine (0.68 ± 0.10) > (-)-iboganine (0.95 ± 0.10) > (±)-18-methoxycoronaridine [(±)-18-MC] (1.47 ± 0.21) > (-)-voacangine (2.28 ± 0.33) > (±)-18-methylaminocoronaridine [(±)-18-MAC] (2.62 ± 0.57 μM) ~ (±)-18-hydroxycoronaridine [(±)-18-HC] (2.81 ± 0.54) > (-)-noriboganine (6.82 ± 0.78). A good linear correlation (r2 = 0.771) between the calculated IC50 values and their polar surface area was found, suggesting that this is an important structural feature for the activity of coronaridine congeners. The radioligand competition results indicate that (±)-18-MC and (-)-iboganine partially inhibit [3H]imipramine binding by an allosteric mechanism. Molecular docking and dynamics results suggest that protonated (-)-18-MC binds to luminal [between the phenylalanine/valine (position 13’) and serine (position 6’) rings], non-luminal (between 4-M1, 3/4-M2, and3-M3), and intersubunit (between 3-M1 and 3/4-M2) sites. Collectively our data indicate that coronaridine congeners inhibit hα3β4 AChRs by blocking the ion channel’s lumen and probably by additional negative allosteric mechanisms by interacting with a series of non-luminal sites.

Item Type:	Article
Date Deposited:	12 May 2016 23:45
Last Modified:	12 May 2016 23:45
URI:	https://oak.novartis.com/id/eprint/22761