The Journal of biological chemistry
May 25, 2012
Simon Bulling, Klaus Schicker, Yuan-Wei Zhang et al.
124 citations
Ibogaine, a hallucinogenic alkaloid proposed as a treatment for opiate withdrawal, inhibits the serotonin transporter (SERT) through a noncompetitive mechanism, unlike all other known inhibitors which compete with serotonin. It binds to a distinct site accessible from the cell exterior, not the substrate-binding site, and increases accessibility in the cytoplasmic permeation pathway. Ibogaine also noncompetitively inhibits the dopamine transporter (DAT) and blocks substrate-induced currents in both transporters. The inhibition is not reversed by increasing substrate concentration, and ibogaine does not form a long-lived complex with SERT but binds directly to the inward-open conformation. A kinetic model distinguishes ibogaine's noncompetitive action from cocaine's competitive action.
Biological Chemistry
January 2, 2011
Thomas Steinkellner, Michael Freissmuth, Harald H. Sitte et al.
112 citations
Amphetamines like speed, ice, and ecstasy are widely abused for their euphoric and stimulant effects. While animal studies show strong evidence that MDMA causes chronic neurotoxicity, the physiological consequences in humans remain unclear. Differences in metabolism and pharmacokinetics between species and animal strains make it difficult to design realistic human dose paradigms in animal research. This review examines amphetamine toxicity, especially MDMA toxicity, in the context of human disease, setting aside confounding factors such as polydrug use and drug purity.
Handbook of experimental pharmacology
January 1, 2018
Michael Freissmuth, Thomas Stockner, Sonja Sucic
44 citations
Mutations in solute carrier 6 (SLC6) family transporters cause misfolding and lead to diseases such as infantile dystonia (from dopamine transporter mutations), mental retardation (from creatine transporter mutations), and hyperekplexia (from glycine transporter mutations). Compounds that correct these folding defects, known as pharmacochaperones, were first discovered in serotonin transporter mutants, where ibogaine and its metabolite noribogaine were found to rescue folding-deficient mutants. Additional compounds have since been identified that restore function in dopamine transporter mutants. These agents not only offer therapeutic potential for affected children but also serve as tools to study transporter folding, potentially enabling the rational design of pharmacochaperones.
ACS pharmacology & translational science
April 9, 2021
Shreyas Bhat, Daryl A Guthrie, Ameya Kasture et al.
37 citations
Protein misfolding caused by missense mutations is rare but collectively leads to serious folding diseases. Ibogaine and noribogaine can correct folding defects in the dopamine transporter (DAT) but rescue only a limited number of DAT mutants linked to infantile Parkinsonism and dystonia. By reconfiguring the ibogaine ring system, a series of analogs were generated and tested for binding to wild-type transporters and for rescuing two synthetic folding-deficient mutants. The most active tropane-based analog (9b) acted as an effective pharmacochaperone in vivo in Drosophila carrying a DAT mutation and rescued 6 out of 13 disease-associated human DAT mutant proteins in vitro, identifying a novel lead compound with potential for medication development for patients with DAT mutations.
bioRxiv (Cold Spring Harbor Laboratory)
July 14, 2020
Shreyas Bhat, Daryl A. Guthrie, Ameya Kasture et al.
3 citations
preprint
A novel tropane-based compound, 9b, corrects folding defects in the dopamine transporter (DAT) caused by specific mutations linked to infantile Parkinsonism and dystonia. By reconfiguring the ibogaine ring system, researchers created analogs that bind to wild-type transporters and rescue two synthetic folding-deficient mutants, SERT-PG 601,602 AA and DAT-PG 584,585 AA. The most active analog, 9b, was effective as a pharmacochaperone in fruit flies carrying the DAT-PG 584,585 AA mutation and rescued six out of 13 disease-associated human DAT mutants in cell-based tests. This compound represents a promising lead for developing medications for patients with DAT mutations.