Structure-Activity Relationships of Dopamine Transporter Pharmacological Chaperones

Abstract

Mutations in the dopamine transporter gene (SLC6A3) have been implicated in many human diseases. Among these is the infantile parkinsonism-dystonia known as Dopamine Transporter Deficiency Syndrome (DTDS). Afflicted individuals have minimal to no functional dopamine transporter protein. This is primarily due to retention of misfolded disease-causing dopamine transporter variants. This results in a variety of severe motor symptoms in patients and the disease ultimately leads to death in adolescence or young adulthood. Though no treatment is currently available, pharmacological chaperones targeting the dopamine transporter have been shown to rescue select DTDS disease-causing variants. Previous work has identified two DAT pharmacological chaperones with moderate potency and efficacy: bupropion and ibogaine. In this study, we carried out structure-activity relationships (SARs) for bupropion and ibogaine with the goal of identifying the chemical features required for pharmacological chaperone activity. Our results show that the isoquinuclidine substituent of ibogaine and its analogs is an important feature for pharmacological chaperone efficacy. For bupropion, the secondary amine group is essential for pharmacological chaperone activity. Lastly, we describe additional ibogaine and bupropion analogs with varying chemical modifications and variable pharmacological chaperone efficacies at the dopamine transporter. Our results contribute to the design and refinement of future dopamine transporter pharmacological chaperones with improved efficacies and potencies.

Tricyclic and tetracyclic antidepressants upregulate VMAT2 activity and rescue disease-causing VMAT2 variants

“…In stable-transfected HEK293 cells, the total VMAT2 protein levels increased along with an increase in the the mature:immature VMAT2 ratio, suggesting that tricyclics and tetracyclics promote VMAT2 protein maturation ( Figures 3B-G ). This phenomenon of inhibitors promoting transporter maturation has previously been reported for ibogaine, bupropion, and their analogues on DAT, and ibogaine and its analogues on SERT [22, 26–29, 31]. Ibogaine and ibogaine analogues were proposed to act as pharmacological chaperones that bind to the inward-facing conformation of DAT and SERT and stabilize the folding of the transporters.…”

A mechanism of uncompetitive inhibition of the serotonin transporter

“…We note, though, that noribogaine was more efficacious as a pharmacochaperone: E max of pharmacochaperoning, i.e., the extent to which substrate transport was restored at saturating concentrations - was consistently higher with noribogaine than with ECSI#6. Variable efficacy of pharmacochaperones was noted previously [30,48]. Efficacy also depends on the nature of the mutation: individual mutants are stalled at different positions within the energy landscape of the folding trajectory [27–29,46].…”

“…This conjecture is supported by the observation that mutations, which trap SERT in the inward-facing state, act as second site suppressors: they restore export from the endoplasmic reticulum and cell surface delivery of folding-deficient mutants [46]. In addition, many compounds, which act as pharmacochaperones on SERT or DAT, are atypical inhibitors with appreciable affinity for the inward-facing state [11,12,28,30,32,33,47,48]. Thus, based on its preferential binding to the inward-facing state of SERT, ECSI#6 was predicted to have pharmacochaperoning activity.…”

“…Thus, individual mutants must differ in their susceptibility to pharmacochaperoning. In addition, in a given folding-deficient mutant, closely related compounds differ in E max of pharmacochaperoning [13,30,48]. Thus, pharmacochaperoning efficacy is also an intrinsic property of a compound linked to its chemical structure.…”

The Bright Side of Psychedelics: Latest Advances and Challenges in Neuropharmacology

“…However, ibogaine and its derivatives do not show specific pharmacological profiles. Indeed, an inhibitory action was also highlighted on the monoamine transporters [ 59 ]. The high affinity of ibogaine and its derivatives to monoamine transporters could explain the observed antidepressant effects, as has also been elucidated by structural studies (see the Structural and Computational Studies section).…”