Abstract
Currently, there are no FDA-approved medications for the treatment of psychostimulant use disorders (PSUD). We have previously discovered “atypical” dopamine transporter (DAT) inhibitors that do not display psychostimulant-like behaviors and may be useful as medications to treat PSUD. Lead candidates (e.g., JJC8-091, 1) have shown promising in vivo profiles in rodents; however, reducing hERG (human ether-à-go-go-related gene) activity, a predictor of cardiotoxicity, has remained a challenge. Herein, a series of 30 (([1,1′-biphenyl]-2-yl)methyl)sulfinylalkyl alicyclic amines was synthesized and evaluated for DAT and serotonin transporter (SERT) binding affinities. A subset of analogues was tested for hERG activity, and the IC50 values were compared to those predicted by our hERG QSAR models, which showed robust predictive power. Multiparameter optimization scores (MPO > 3) indicated central nervous system (CNS) penetrability. Finally, comparison of affinities in human DAT and its Y156F and Y335A mutants suggested that several compounds prefer an inward facing conformation indicating an atypical DAT inhibitor profile.
Original language | English |
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Journal | ACS Pharmacology and Translational Science |
Volume | 7 |
Issue number | 2 |
Pages (from-to) | 515-532 |
Number of pages | 18 |
ISSN | 2575-9108 |
DOIs | |
Publication status | Published - 2024 |
Bibliographical note
Publisher Copyright:© 2024 American Chemical Society
Keywords
- atypical dopamine transporter inhibitors
- cocaine
- DAT
- dopamine transporter
- hERG
- human ether-à-go-go-related gene
- MPO
- multiparameter optimization score
- psychostimulants
- serotonin transporter