Coronaridine congeners inhibit human α3β4 nicotinic acetylcholine receptors by interacting with luminal and non-luminal sites

Hugo R. Arias, Katarzyna M. Targowska-Duda, Dominik Feuerbach, Krzysztof Jozwiak

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

To characterize the interaction of coronaridine congeners with human (h) α3β4 nicotinic acetylcholine receptors (AChRs), structural and functional approaches were used. The Ca2+ influx results established that coronaridine congeners noncompetitively inhibit hα3β4 AChRs with the following potency (IC50's in μM) sequence: (-)-ibogamine (0.62 ± 0.23) ∼ (+)-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 μM) ∼ (±)-18-hydroxycoronaridine (2.81 ± 0.54) > (-)-noribogaine (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 its activity. The radioligand competition results indicate that (±)-18-MC and (-)-ibogaine partially inhibit [3H]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., β4-Phe255 (phenylalanine/valine ring; position 13′), and α3-Leu250 and β4-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 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.

Original languageEnglish
Pages (from-to)81-90
Number of pages10
JournalInternational Journal of Biochemistry and Cell Biology
Volume65
DOIs
StatePublished - 12 Jun 2015
Externally publishedYes

Fingerprint

Ibogaine
Nicotinic Receptors
Cholinergic Receptors
Inhibitory Concentration 50
Imipramine
Valine
Molecular Dynamics Simulation
Phenylalanine
Ion Channels
Leucine
Hydroxyl Radical
Computer Simulation
Molecular dynamics
Hydrogen
Hydrogen bonds
Nitrogen
Mutation
coronardine
ibogamine

Keywords

  • Allosteric modulation
  • Conformational states
  • Coronaridine congeners
  • In silico mutations
  • Molecular modeling
  • Structureactivity relationship
  • α3β4 Nicotinic acetylcholine receptor

Cite this

@article{0ecf0d00068b45ce8718ae1c9d49a66a,
title = "Coronaridine congeners inhibit human α3β4 nicotinic acetylcholine receptors by interacting with luminal and non-luminal sites",
abstract = "To characterize the interaction of coronaridine congeners with human (h) α3β4 nicotinic acetylcholine receptors (AChRs), structural and functional approaches were used. The Ca2+ influx results established that coronaridine congeners noncompetitively inhibit hα3β4 AChRs with the following potency (IC50's in μM) sequence: (-)-ibogamine (0.62 ± 0.23) ∼ (+)-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 μM) ∼ (±)-18-hydroxycoronaridine (2.81 ± 0.54) > (-)-noribogaine (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 its activity. The radioligand competition results indicate that (±)-18-MC and (-)-ibogaine partially inhibit [3H]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., β4-Phe255 (phenylalanine/valine ring; position 13′), and α3-Leu250 and β4-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 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.",
keywords = "Allosteric modulation, Conformational states, Coronaridine congeners, In silico mutations, Molecular modeling, Structureactivity relationship, α3β4 Nicotinic acetylcholine receptor",
author = "Arias, {Hugo R.} and Targowska-Duda, {Katarzyna M.} and Dominik Feuerbach and Krzysztof Jozwiak",
year = "2015",
month = "6",
day = "12",
doi = "10.1016/j.biocel.2015.05.015",
language = "English",
volume = "65",
pages = "81--90",
journal = "International Journal of Biochemistry and Cell Biology",
issn = "1357-2725",

}

Coronaridine congeners inhibit human α3β4 nicotinic acetylcholine receptors by interacting with luminal and non-luminal sites. / Arias, Hugo R.; Targowska-Duda, Katarzyna M.; Feuerbach, Dominik; Jozwiak, Krzysztof.

In: International Journal of Biochemistry and Cell Biology, Vol. 65, 12.06.2015, p. 81-90.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Coronaridine congeners inhibit human α3β4 nicotinic acetylcholine receptors by interacting with luminal and non-luminal sites

AU - Arias, Hugo R.

AU - Targowska-Duda, Katarzyna M.

AU - Feuerbach, Dominik

AU - Jozwiak, Krzysztof

PY - 2015/6/12

Y1 - 2015/6/12

N2 - To characterize the interaction of coronaridine congeners with human (h) α3β4 nicotinic acetylcholine receptors (AChRs), structural and functional approaches were used. The Ca2+ influx results established that coronaridine congeners noncompetitively inhibit hα3β4 AChRs with the following potency (IC50's in μM) sequence: (-)-ibogamine (0.62 ± 0.23) ∼ (+)-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 μM) ∼ (±)-18-hydroxycoronaridine (2.81 ± 0.54) > (-)-noribogaine (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 its activity. The radioligand competition results indicate that (±)-18-MC and (-)-ibogaine partially inhibit [3H]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., β4-Phe255 (phenylalanine/valine ring; position 13′), and α3-Leu250 and β4-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 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.

AB - To characterize the interaction of coronaridine congeners with human (h) α3β4 nicotinic acetylcholine receptors (AChRs), structural and functional approaches were used. The Ca2+ influx results established that coronaridine congeners noncompetitively inhibit hα3β4 AChRs with the following potency (IC50's in μM) sequence: (-)-ibogamine (0.62 ± 0.23) ∼ (+)-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 μM) ∼ (±)-18-hydroxycoronaridine (2.81 ± 0.54) > (-)-noribogaine (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 its activity. The radioligand competition results indicate that (±)-18-MC and (-)-ibogaine partially inhibit [3H]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., β4-Phe255 (phenylalanine/valine ring; position 13′), and α3-Leu250 and β4-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 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.

KW - Allosteric modulation

KW - Conformational states

KW - Coronaridine congeners

KW - In silico mutations

KW - Molecular modeling

KW - Structureactivity relationship

KW - α3β4 Nicotinic acetylcholine receptor

UR - http://www.scopus.com/inward/record.url?scp=84930948662&partnerID=8YFLogxK

U2 - 10.1016/j.biocel.2015.05.015

DO - 10.1016/j.biocel.2015.05.015

M3 - Article

C2 - 26022277

AN - SCOPUS:84930948662

VL - 65

SP - 81

EP - 90

JO - International Journal of Biochemistry and Cell Biology

JF - International Journal of Biochemistry and Cell Biology

SN - 1357-2725

ER -