A tropane-based ibogaine analog rescues folding-deficient SERT and DAT
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.