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.
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 FOCUS and TEAM research subsidy from the Foundation for Polish Science (to K.J.), and by the National Institute on Drug Addiction (NIDA) grant DA016283 (to S.D.G.). This research was also supported in part by the Intramural Research Program of the NIH, National Institute on Aging . The authors give thanks to NIDA (NIH, Bethesda, Maryland, USA) for the gift of [ 3 H]Ibogaine, ibogaine, and phencyclidine, and to Jorgelina L. Arias Castillo and Paulina Iacoban for their technical assistance.
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 -