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.
Comparable studies
Other experimental studies on ibogaine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Ibogaine, a noncompetitive inhibitor of serotonin transport, acts by stabilizing the cytoplasm-facing state of the transporter. In vitro (SERT) | 2007 | Laboratory study | |
| Mechanisms of action of ibogaine and harmaline congeners based on radioligand binding studies. | 1992 | Laboratory study | |
| The mechanistic basis for noncompetitive ibogaine inhibition of serotonin and dopamine transporters. | 2012 | Experimental study | |
| Identification of a primary metabolite of ibogaine that targets serotonin transporters and elevates serotonin. | 1995 | Experimental study | |
| Ibogaine and its congeners are sigma 2 receptor-selective ligands with moderate affinity. | 1995 | Laboratory study |
Citations in the library
Cited by 10
- Main targets of ibogaine and noribogaine associated with its putative anti-addictive effects: A mechanistic overview. Journal of Psychopharmacology December 1, 2023
- Bedside to bench: the outlook for psychedelic research Frontiers in Pharmacology October 2, 2023
- Oxa-Iboga alkaloids lack cardiac risk and disrupt opioid use in animal models. Nature Communications September 20, 2024
- Structure-Activity Relationships of Dopamine Transporter Pharmacological Chaperones. Frontiers in Cellular Neuroscience 2022
- Novel Class of Psychedelic Iboga Alkaloids Disrupts Opioid Use bioRxiv (Cold Spring Harbor Laboratory) July 23, 2021
and 5 more in the library
Cites 16
- Serotonin transporter-ibogaine complexes illuminate mechanisms of inhibition and transport. Nature May 1, 2019
- Effects and aftereffects of ibogaine on morphine self-administration in rats. European Journal of Pharmacology April 3, 1991
- Effects of iboga alkaloids on morphine and cocaine self-administration in rats: relationship to tremorigenic effects and to effects on dopamine release in nucleus accumbens and striatum. Brain Research September 19, 1994
- Treatment of opioid use disorder with ibogaine: detoxification and drug use outcomes. The American Journal of Drug and Alcohol Abuse 2018
- Ibogaine treatment outcomes for opioid dependence from a twelve-month follow-up observational study. The American Journal of Drug and Alcohol Abuse 2018
and 11 more in the library