Interaction of 18-methoxycoronaridine with nicotinic acetylcholine receptors in different conformational states

Hugo R. Arias, Avraham Rosenberg, Dominik Feuerbach, Katarzyna M. Targowska-Duda, Ryszard Maciejewski, Krzysztof Jozwiak, Ruin Moaddel, Stanley D. Glick, Irving W. Wainer

Research output: Contribution to journalArticle

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Abstract

The interaction of 18-methoxycoronaridine (18-MC) with nicotinic acetylcholine receptors (AChRs) was compared with that for ibogaine and phencyclidine (PCP). The results established that 18-MC: (a) is more potent than ibogaine and PCP inhibiting (±)-epibatidine-induced AChR Ca2+ influx. The potency of 18-MC is increased after longer pre-incubation periods, which is in agreement with the enhancement of [3H]cytisine binding to resting but activatable Torpedo AChRs, (b) binds to a single site in the Torpedo AChR with high affinity and inhibits [3H]TCP binding to desensitized AChRs in a steric fashion, suggesting the existence of overlapping sites. This is supported by our docking results indicating that 18-MC interacts with a domain located between the serine (position 6′) and valine (position 13′) rings, and (c) inhibits [3H]TCP, [3H]ibogaine, and [3H]18-MC binding to desensitized AChRs with higher affinity compared to resting AChRs. This can be partially attributed to a slower dissociation rate from the desensitized AChR compared to that from the resting AChR. The enthalpic contribution is more important than the entropic contribution when 18-MC binds to the desensitized AChR compared to that for the resting AChR, and vice versa. Ibogaine analogs inhibit the AChR by interacting with a luminal domain that is shared with PCP, and by inducing desensitization.

Original languageEnglish
Pages (from-to)1153-1163
Number of pages11
JournalBiochimica et Biophysica Acta - Biomembranes
Volume1798
Issue number6
DOIs
StatePublished - 1 Jun 2010
Externally publishedYes

Fingerprint

Nicotinic Receptors
Cholinergic Receptors
Ibogaine
Torpedo
epibatidine
18-methoxycoronaridine
Phencyclidine
Valine
Serine

Keywords

  • 18-Methoxycoronaridine
  • Conformational state
  • Ibogaine analog
  • Nicotinic acetylcholine receptor
  • Noncompetitive antagonist

Cite this

Arias, Hugo R. ; Rosenberg, Avraham ; Feuerbach, Dominik ; Targowska-Duda, Katarzyna M. ; Maciejewski, Ryszard ; Jozwiak, Krzysztof ; Moaddel, Ruin ; Glick, Stanley D. ; Wainer, Irving W. / Interaction of 18-methoxycoronaridine with nicotinic acetylcholine receptors in different conformational states. In: Biochimica et Biophysica Acta - Biomembranes. 2010 ; Vol. 1798, No. 6. pp. 1153-1163.
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abstract = "The interaction of 18-methoxycoronaridine (18-MC) with nicotinic acetylcholine receptors (AChRs) was compared with that for ibogaine and phencyclidine (PCP). The results established that 18-MC: (a) is more potent than ibogaine and PCP inhibiting (±)-epibatidine-induced AChR Ca2+ influx. The potency of 18-MC is increased after longer pre-incubation periods, which is in agreement with the enhancement of [3H]cytisine binding to resting but activatable Torpedo AChRs, (b) binds to a single site in the Torpedo AChR with high affinity and inhibits [3H]TCP binding to desensitized AChRs in a steric fashion, suggesting the existence of overlapping sites. This is supported by our docking results indicating that 18-MC interacts with a domain located between the serine (position 6′) and valine (position 13′) rings, and (c) inhibits [3H]TCP, [3H]ibogaine, and [3H]18-MC binding to desensitized AChRs with higher affinity compared to resting AChRs. This can be partially attributed to a slower dissociation rate from the desensitized AChR compared to that from the resting AChR. The enthalpic contribution is more important than the entropic contribution when 18-MC binds to the desensitized AChR compared to that for the resting AChR, and vice versa. Ibogaine analogs inhibit the AChR by interacting with a luminal domain that is shared with PCP, and by inducing desensitization.",
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Arias, HR, Rosenberg, A, Feuerbach, D, Targowska-Duda, KM, Maciejewski, R, Jozwiak, K, Moaddel, R, Glick, SD & Wainer, IW 2010, 'Interaction of 18-methoxycoronaridine with nicotinic acetylcholine receptors in different conformational states', Biochimica et Biophysica Acta - Biomembranes, vol. 1798, no. 6, pp. 1153-1163. https://doi.org/10.1016/j.bbamem.2010.03.013

Interaction of 18-methoxycoronaridine with nicotinic acetylcholine receptors in different conformational states. / Arias, Hugo R.; Rosenberg, Avraham; Feuerbach, Dominik; Targowska-Duda, Katarzyna M.; Maciejewski, Ryszard; Jozwiak, Krzysztof; Moaddel, Ruin; Glick, Stanley D.; Wainer, Irving W.

In: Biochimica et Biophysica Acta - Biomembranes, Vol. 1798, No. 6, 01.06.2010, p. 1153-1163.

Research output: Contribution to journalArticle

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T1 - Interaction of 18-methoxycoronaridine with nicotinic acetylcholine receptors in different conformational states

AU - Arias, Hugo R.

AU - Rosenberg, Avraham

AU - Feuerbach, Dominik

AU - Targowska-Duda, Katarzyna M.

AU - Maciejewski, Ryszard

AU - Jozwiak, Krzysztof

AU - Moaddel, Ruin

AU - Glick, Stanley D.

AU - Wainer, Irving W.

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N2 - The interaction of 18-methoxycoronaridine (18-MC) with nicotinic acetylcholine receptors (AChRs) was compared with that for ibogaine and phencyclidine (PCP). The results established that 18-MC: (a) is more potent than ibogaine and PCP inhibiting (±)-epibatidine-induced AChR Ca2+ influx. The potency of 18-MC is increased after longer pre-incubation periods, which is in agreement with the enhancement of [3H]cytisine binding to resting but activatable Torpedo AChRs, (b) binds to a single site in the Torpedo AChR with high affinity and inhibits [3H]TCP binding to desensitized AChRs in a steric fashion, suggesting the existence of overlapping sites. This is supported by our docking results indicating that 18-MC interacts with a domain located between the serine (position 6′) and valine (position 13′) rings, and (c) inhibits [3H]TCP, [3H]ibogaine, and [3H]18-MC binding to desensitized AChRs with higher affinity compared to resting AChRs. This can be partially attributed to a slower dissociation rate from the desensitized AChR compared to that from the resting AChR. The enthalpic contribution is more important than the entropic contribution when 18-MC binds to the desensitized AChR compared to that for the resting AChR, and vice versa. Ibogaine analogs inhibit the AChR by interacting with a luminal domain that is shared with PCP, and by inducing desensitization.

AB - The interaction of 18-methoxycoronaridine (18-MC) with nicotinic acetylcholine receptors (AChRs) was compared with that for ibogaine and phencyclidine (PCP). The results established that 18-MC: (a) is more potent than ibogaine and PCP inhibiting (±)-epibatidine-induced AChR Ca2+ influx. The potency of 18-MC is increased after longer pre-incubation periods, which is in agreement with the enhancement of [3H]cytisine binding to resting but activatable Torpedo AChRs, (b) binds to a single site in the Torpedo AChR with high affinity and inhibits [3H]TCP binding to desensitized AChRs in a steric fashion, suggesting the existence of overlapping sites. This is supported by our docking results indicating that 18-MC interacts with a domain located between the serine (position 6′) and valine (position 13′) rings, and (c) inhibits [3H]TCP, [3H]ibogaine, and [3H]18-MC binding to desensitized AChRs with higher affinity compared to resting AChRs. This can be partially attributed to a slower dissociation rate from the desensitized AChR compared to that from the resting AChR. The enthalpic contribution is more important than the entropic contribution when 18-MC binds to the desensitized AChR compared to that for the resting AChR, and vice versa. Ibogaine analogs inhibit the AChR by interacting with a luminal domain that is shared with PCP, and by inducing desensitization.

KW - 18-Methoxycoronaridine

KW - Conformational state

KW - Ibogaine analog

KW - Nicotinic acetylcholine receptor

KW - Noncompetitive antagonist

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M3 - Article

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