Journal
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
Volume 65, Issue -, Pages 81-90Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.biocel.2015.05.015
Keywords
alpha 3 beta 4 Nicotinic acetylcholine receptor; Coronaridine congeners; Allosteric modulation; Molecular modeling; Conformational states; Structure-activity relationship; In silico mutations
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Funding
- Foundation for Polish Science, Poland [TEAM 2009/4-5]
- National Science Center, Poland [UMO-2013/09/D/NZ7/04549]
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To characterize the interaction of coronaridine congeners with human (h) 03134 nicotinic acetylcholine receptors (AChRs), structural and functional approaches were used. The Ca2+ influx results established that coronaridine congeners noncompetitively inhibit h alpha 3 beta 4 AChRs with the following potency (IC50's in mu M) sequence: (-)-ibogamine (0.62 +/- 0.23)similar to(+)-catharanthine (0.68 +/- 0.10)>(-)-ibogaine (0.95 +/- 0.10)>(+/-)-18-methoxycoronaridine [(+/-)-18-MC] (1.47 +/- 0.21) > (-)-voacangine (2.28 +/- 0.33)>(+/-)-18-methylaminocoronaridine (2.62 +/- 0.57 mu M)similar to(+/-)-18-hydroxycoronaridine (2.81 +/- 0.54)>(-)-noribogaine (6.82 +/- 0.78). A good linear correlation (r(2) = 0.771) between the calculated IC50 values and their polar surface area was found, suggesting that this is an important structural feature for its activity. The radioligand competition results indicate that (+/-)-18-MC and (-)-ibogaine partially inhibit [H-3]imipramine binding by an allosteric mechanism. Molecular docking, molecular dynamics, and in silico mutation results suggest that protonated (-)-18-MC binds to luminal [i.e., beta 4-Phe255 (phenylalanine/valine ring; position 13'), and alpha 3-Leu250 and beta 4-Leu251 (leucine ring; position 9')], non-luminal, and intersubunit sites. The pharmacophore model suggests that nitrogens from the ibogamine core as well as methylamino, hydroxyl, and methoxyl moieties at position 18 form hydrogen bonds. Collectively our data indicate that coronaridine congeners inhibit h alpha 3 beta 4 AChRs by blocking the ion channel's lumen and probably by additional negative allosteric mechanisms by interacting with a series of non-luminal sites. (C) 2015 Elsevier Ltd. All rights reserved.
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