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 language | English |
|---|---|
| Pages (from-to) | 1153-1163 |
| Number of pages | 11 |
| Journal | Biochimica et Biophysica Acta - Biomembranes |
| Volume | 1798 |
| Issue number | 6 |
| DOIs | |
| State | Published - 1 Jun 2010 |
| Externally published | Yes |
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Keywords
- 18-Methoxycoronaridine
- Conformational state
- Ibogaine analog
- Nicotinic acetylcholine receptor
- Noncompetitive antagonist
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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 journal › Article
TY - JOUR
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.
PY - 2010/6/1
Y1 - 2010/6/1
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
UR - http://www.scopus.com/inward/record.url?scp=77952583243&partnerID=8YFLogxK
U2 - 10.1016/j.bbamem.2010.03.013
DO - 10.1016/j.bbamem.2010.03.013
M3 - Article
C2 - 20303928
AN - SCOPUS:77952583243
VL - 1798
SP - 1153
EP - 1163
JO - Biochimica et Biophysica Acta - Biomembranes
JF - Biochimica et Biophysica Acta - Biomembranes
SN - 0005-2736
IS - 6
ER -