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.
The FASEB Journal
April 1, 2013
Jonathan M. Slezak, Melanie Mueller, George A Ricaurte et al.
MDMA's behavioral effects are primarily due to central nervous system actions, not peripheral ones. In rats trained to distinguish MDMA from saline, the drug produced dose-related increases in drug-appropriate responses. A quaternary analog of MDMA (qMDMA), which cannot cross the blood-brain barrier, did not substitute for MDMA when given peripherally, but partially substituted when infused directly into the brain. This validates qMDMA as a tool for separating central from peripheral effects of MDMA.