TY - JOUR
T1 - Structure-activity relationship of ibogaine analogs interacting with nicotinic acetylcholine receptors in different conformational states
AU - Arias, Hugo R.
AU - Feuerbach, Dominik
AU - Targowska-Duda, Katarzyna M.
AU - Jozwiak, Krzysztof
N1 - Funding Information:
This research was supported by grants from the Science Foundation Arizona and Stardust Foundation and from the Office of Research and Sponsored Programs, Midwestern University (to H.R.A.) , by a grant from the Polish Ministry of Science and Higher Education (No. NN 405297036) and by the TEAM research subsidy from the Foundation for Polish Science (to K.J.). The authors thank to NIDA (NIH, Bethesda, Maryland, USA) for the gift of ibogaine and phencyclidine, to Dr. Kuehne (Department of Chemistry, University of Vermont, VT, USA) and Dr. Borschberg (Eidgenössische Technische Hochschule, Switzerland) for their gifts of ibogaine analogs, and to Paulina Iacoban for their technical assistance.
PY - 2011/9/1
Y1 - 2011/9/1
N2 - The interaction of ibogaine analogs with nicotinic acetylcholine receptors (AChRs) in different conformational states was studied by functional and structural approaches. The results established that ibogaine analogs: (a) inhibit (±)-epibatidine-induced Ca 2+ influx in human embryonic muscle AChRs with the following potency sequence (IC 50 in μM): (±)-18-methylaminocoronaridine (5.9 ± 0.3) ∼ (±)-18-methoxycoronaridine (18-MC) (6.8 ± 0.8) > (-)-ibogaine (17 ± 3) ∼ (+)-catharanthine (20 ± 1) > (±)-albifloranine (46 ± 13), (b) bind to the [ 3H]TCP binding site with higher affinity when the Torpedo AChR is in the desensitized state compared to that in the resting state. Similar results were obtained using [ 3H]18-MC. These and docking results suggest a steric interaction between TCP and ibogaine analogs for the same site, (c) enhance [ 3H]cytisine binding to resting but not to desensitized AChRs, with desensitizing potencies (apparent EC 50) that correlate very well with the pK i values in the desensitized state, and (d) there are good bilinear correlations between the ligand molecular volumes and their affinities in the desensitized and resting states, with an optimal volume of ∼345 3 for the ibogaine site. These results indicate that the size of the binding sites for ibogaine analogs, located between the serine and nonpolar rings and shared with TCP, is an important structural feature for binding and for inducing desensitization.
AB - The interaction of ibogaine analogs with nicotinic acetylcholine receptors (AChRs) in different conformational states was studied by functional and structural approaches. The results established that ibogaine analogs: (a) inhibit (±)-epibatidine-induced Ca 2+ influx in human embryonic muscle AChRs with the following potency sequence (IC 50 in μM): (±)-18-methylaminocoronaridine (5.9 ± 0.3) ∼ (±)-18-methoxycoronaridine (18-MC) (6.8 ± 0.8) > (-)-ibogaine (17 ± 3) ∼ (+)-catharanthine (20 ± 1) > (±)-albifloranine (46 ± 13), (b) bind to the [ 3H]TCP binding site with higher affinity when the Torpedo AChR is in the desensitized state compared to that in the resting state. Similar results were obtained using [ 3H]18-MC. These and docking results suggest a steric interaction between TCP and ibogaine analogs for the same site, (c) enhance [ 3H]cytisine binding to resting but not to desensitized AChRs, with desensitizing potencies (apparent EC 50) that correlate very well with the pK i values in the desensitized state, and (d) there are good bilinear correlations between the ligand molecular volumes and their affinities in the desensitized and resting states, with an optimal volume of ∼345 3 for the ibogaine site. These results indicate that the size of the binding sites for ibogaine analogs, located between the serine and nonpolar rings and shared with TCP, is an important structural feature for binding and for inducing desensitization.
KW - Conformational states
KW - Ibogaine analogs
KW - Molecular modeling
KW - Nicotinic acetylcholine receptors
KW - Noncompetitive antagonists
KW - Structure-activity relationship
UR - http://www.scopus.com/inward/record.url?scp=79960899194&partnerID=8YFLogxK
U2 - 10.1016/j.biocel.2011.05.011
DO - 10.1016/j.biocel.2011.05.011
M3 - Article
C2 - 21642011
AN - SCOPUS:79960899194
SN - 1357-2725
VL - 43
SP - 1330
EP - 1339
JO - International Journal of Biochemistry and Cell Biology
JF - International Journal of Biochemistry and Cell Biology
IS - 9
ER -