Tropane-Based Ibogaine Analog Rescues Folding-Deficient Serotonin and Dopamine Transporters.
Shreyas Bhat, Daryl A. Guthrie, Ameya Kasture, Ali El-Kasaby, Jianjing Cao, Alessandro Bonifazi, Therese Ku, Jolynn B. Giancola, Thomas Hummel, Michael Freissmuth, Amy Hauck Newman
ACS Pharmacology & Translational Science April 9, 2021 DOI: 10.1021/acsptsci.0c00102 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Drosophila harboring the DAT-PG584,585AA mutation and human DAT mutant proteins in vitro |
| Interventions | ibogaine noribogaine |
| Topics | Ibogaine Serotonin |
| Keywords | Protein misfolding Protein folding diseases Proteinopathy Proteostasis Conformational diseases Drug discovery Medication development Pharmaceutical development Novel compounds Therapeutic agents Neurotransporters Serotonin transporter Dopamine transporter Brain chemical transporters Neurological function Ibogaine analogs Tropane compounds Ibogaine derivatives Medicinal chemistry |
| Citations | 37 |
| Key findings | A tropane-based ibogaine analog (9b) rescued 6 out of 13 disease-associated human DAT mutant proteins in vitro and acted as an effective pharmacochaperone in vivo in Drosophila. |
Abstract
Missense mutations that give rise to protein misfolding are rare, but collectively, defective protein folding diseases are consequential. Folding deficiencies are amenable to pharmacological correction (pharmacochaperoning), but the underlying mechanisms remain enigmatic. Ibogaine and its active metabolite noribogaine correct folding defects in the dopamine transporter (DAT), but they rescue only a very limited number of folding-deficient DAT mutant proteins, which give rise to infantile Parkinsonism and dystonia. Herein, a series of analogs was generated by reconfiguring the complex ibogaine ring system and exploring the structural requirements for binding to wild-type transporters, as well as for rescuing two equivalent synthetic folding-deficient mutants, SERT-PG601,602AA and DAT-PG584,585AA. The most active tropane-based analog (9b) was also an effective pharmacochaperone in vivo in Drosophila harboring the DAT-PG584,585AA mutation and rescued 6 out of 13 disease-associated human DAT mutant proteins in vitro. Hence, a novel lead pharmacochaperone has been identified that demonstrates medication development potential for patients harboring DAT mutations.