Abstract
We compared the interaction of several catharanthine alkaloids including, ibogaine, vincristine, and vinblastine, with that for the noncompetitive antagonist phencyclidine (PCP) at muscle nicotinic acetylcholine receptors (AChRs) in different conformational states. The results established that catharanthine alkaloids: (a) inhibit, in a noncompetitive manner, (±)-epibatidine-induced Ca2+ influx in TE671-hα1β1γδ cells with similar potencies (IC50=17-25μM), (b) inhibit [3H]TCP binding to the desensitized Torpedo AChR with higher affinity compared to the resting AChR, and (c) enhance [3H]cytisine binding to resting but activatable Torpedo AChRs, suggesting desensitizing properties. Interestingly, PCP inhibits [3H]ibogaine binding to the AChR in a steric fashion. This is corroborated by additional docking experiments indicating that the amino groups of neutral ibogaine form hydrogen bonds with the serine ring (position 6'), a location shared with PCP. Since protonated ibogaine forms a salt bridge with one of the acidic residues at the outer ring (position 20'), this ligand could be first attracted to the entrance of the channel by electrostatic interactions. Our data indicate that the catharanthine moiety is a minimum structural requirement for AChR inhibition including, ion channel blocking and desensitization, and that ibogaine and PCP bind to overlapping sites in the desensitized AChR ion channel.
| Original language | English |
|---|---|
| Pages (from-to) | 153-161 |
| Number of pages | 9 |
| Journal | Neurochemistry International |
| Volume | 57 |
| Issue number | 2 |
| DOIs | |
| State | Published - 1 Sep 2010 |
| Externally published | Yes |
Fingerprint
Keywords
- Ca influx
- Catharanthine alkaloids
- Ibogaine
- Molecular modeling
- Nicotinic acetylcholine receptors
- Noncompetitive antagonists
- Nonformational states
- Vinca alkaloids
Cite this
}
Catharanthine alkaloids are noncompetitive antagonists of muscle-type nicotinic acetylcholine receptors. / Arias, Hugo R.; Feuerbach, Dominik; Targowska-Duda, Katarzyna M.; Jozwiak, Krzysztof.
In: Neurochemistry International, Vol. 57, No. 2, 01.09.2010, p. 153-161.Research output: Contribution to journal › Article
TY - JOUR
T1 - Catharanthine alkaloids are noncompetitive antagonists of muscle-type nicotinic acetylcholine receptors
AU - Arias, Hugo R.
AU - Feuerbach, Dominik
AU - Targowska-Duda, Katarzyna M.
AU - Jozwiak, Krzysztof
PY - 2010/9/1
Y1 - 2010/9/1
N2 - We compared the interaction of several catharanthine alkaloids including, ibogaine, vincristine, and vinblastine, with that for the noncompetitive antagonist phencyclidine (PCP) at muscle nicotinic acetylcholine receptors (AChRs) in different conformational states. The results established that catharanthine alkaloids: (a) inhibit, in a noncompetitive manner, (±)-epibatidine-induced Ca2+ influx in TE671-hα1β1γδ cells with similar potencies (IC50=17-25μM), (b) inhibit [3H]TCP binding to the desensitized Torpedo AChR with higher affinity compared to the resting AChR, and (c) enhance [3H]cytisine binding to resting but activatable Torpedo AChRs, suggesting desensitizing properties. Interestingly, PCP inhibits [3H]ibogaine binding to the AChR in a steric fashion. This is corroborated by additional docking experiments indicating that the amino groups of neutral ibogaine form hydrogen bonds with the serine ring (position 6'), a location shared with PCP. Since protonated ibogaine forms a salt bridge with one of the acidic residues at the outer ring (position 20'), this ligand could be first attracted to the entrance of the channel by electrostatic interactions. Our data indicate that the catharanthine moiety is a minimum structural requirement for AChR inhibition including, ion channel blocking and desensitization, and that ibogaine and PCP bind to overlapping sites in the desensitized AChR ion channel.
AB - We compared the interaction of several catharanthine alkaloids including, ibogaine, vincristine, and vinblastine, with that for the noncompetitive antagonist phencyclidine (PCP) at muscle nicotinic acetylcholine receptors (AChRs) in different conformational states. The results established that catharanthine alkaloids: (a) inhibit, in a noncompetitive manner, (±)-epibatidine-induced Ca2+ influx in TE671-hα1β1γδ cells with similar potencies (IC50=17-25μM), (b) inhibit [3H]TCP binding to the desensitized Torpedo AChR with higher affinity compared to the resting AChR, and (c) enhance [3H]cytisine binding to resting but activatable Torpedo AChRs, suggesting desensitizing properties. Interestingly, PCP inhibits [3H]ibogaine binding to the AChR in a steric fashion. This is corroborated by additional docking experiments indicating that the amino groups of neutral ibogaine form hydrogen bonds with the serine ring (position 6'), a location shared with PCP. Since protonated ibogaine forms a salt bridge with one of the acidic residues at the outer ring (position 20'), this ligand could be first attracted to the entrance of the channel by electrostatic interactions. Our data indicate that the catharanthine moiety is a minimum structural requirement for AChR inhibition including, ion channel blocking and desensitization, and that ibogaine and PCP bind to overlapping sites in the desensitized AChR ion channel.
KW - Ca influx
KW - Catharanthine alkaloids
KW - Ibogaine
KW - Molecular modeling
KW - Nicotinic acetylcholine receptors
KW - Noncompetitive antagonists
KW - Nonformational states
KW - Vinca alkaloids
UR - http://www.scopus.com/inward/record.url?scp=77953911700&partnerID=8YFLogxK
U2 - 10.1016/j.neuint.2010.05.007
DO - 10.1016/j.neuint.2010.05.007
M3 - Article
C2 - 20493225
AN - SCOPUS:77953911700
VL - 57
SP - 153
EP - 161
JO - Neurochemistry International
JF - Neurochemistry International
SN - 0197-0186
IS - 2
ER -