title: Interaction of ibogaine with human alpha3beta4-nicotinic acetylcholine receptors in different conformational states.
abstract: The interaction of ibogaine and phencyclidine (PCP) with human (h) alpha3beta4-nicotinic acetylcholine receptors (AChRs) in different conformational states was determined by functional and structural approaches including, radioligand binding assays, Ca2+ influx detections, and thermodynamic and kinetics measurements. The results established that (a) ibogaine inhibits (+/-)-epibatidine-induced Ca2+ influx in h(alpha)3beta4 AChRs with approximately 9-fold higher potency than that for PCP, (b) [3H]ibogaine binds to a single site in the h(alpha)3beta4 AChR ion channel with relatively high affinity (Kd = 0.46 +/- 0.06 microM), and ibogaine inhibits [3H]ibogaine binding to the desensitized h(alpha)3beta4 AChR with slightly higher affinity compared to the resting AChR. This is explained by a slower dissociation rate from the desensitized ion channel compared to the resting ion channel, and (c) PCP inhibits [3H]ibogaine binding to the h(alpha)3beta4 AChR, suggesting overlapping sites. The experimental results correlate with the docking simulations suggesting that ibogaine and PCP interact with a binding domain located between the serine (position 6') and valine/phenylalanine (position 13') rings. This interaction is mediated mainly by van der Waals contacts, which is in agreement with the observed enthalpic contribution determined by non-linear chromatography. However, the calculated entropic contribution also indicates local conformational changes. Collectively our data suggest that ibogaine and PCP bind to overlapping sites located between the serine and valine/phenylalanine rings, to finally block the AChR ion channel, and in the case of ibogaine, to probably maintain the AChR in the desensitized state for longer time.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Midwestern University, 19555 N. 59th Ave., Glendale, AZ 85308, USA. harias@midwestern.edu
authors.forename: Hugo R
authors.initials: HR
authors.lastname: Arias
authors.forename: Avraham
authors.initials: A
authors.lastname: Rosenberg
authors.forename: Katarzyna M
authors.initials: KM
authors.lastname: Targowska-Duda
authors.forename: Dominik
authors.initials: D
authors.lastname: Feuerbach
authors.forename: Xiao Juan
authors.initials: XJ
authors.lastname: Yuan
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Jozwiak
authors.forename: Ruin
authors.initials: R
authors.lastname: Moaddel
authors.forename: Irving W
authors.initials: IW
authors.lastname: Wainer
mesh_terms: D001692:Biological Transport / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D007050:Ibogaine / Q000378:metabolism*; D007700:Kinetics; D010622:Phencyclidine / Q000494:pharmacology; D011485:Protein Binding; D017433:Protein Structure, Secondary; D011725:Pyridines / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D011725:Pyridines; D011978:Receptors, Nicotinic; C403530:nicotinic receptor alpha3beta4; D007050:Ibogaine; D010622:Phencyclidine; C082748:epibatidine; D002118:Calcium