Structural and stereochemical determinants for hGAT3 inhibition: development of novel conformationally constrained and substituted analogs of (S)-isoserine

AbstractThe GABA transporter 3 (GAT3) is a member of the GABA transporter (GAT) family proposed to have a role in regulating tonic inhibition. The GAT3-preferring substrate (S)-isoserine has shown beneficial effects in a mouse model of stroke accompanied by an increased GAT3 expression, indicating a molecular mechanism mediated by GAT3. However, (S)-isoserine is not ideally suited for in vivo studies due to a lack of selectivity and brain permeability. To elucidate the structural determinants of (S)-isoserine for GAT3 inhibition, and to optimize and inform further ligand development, we here present the design, synthesis and pharmacological evaluation of a series of conformationally constrained isoserine analogs with defined stereochemistry. Using [3H]GABA uptake assays at recombinant human GAT3, we identified the azetidine and pyrrolidine analogs (2S,2 ´S)-6 and (2S,2 ´S)-7 as the most potent inhibitors. To further elaborate on the selectivity profile both compounds were tested at all GATs, the taurine transporter (TauT) and GABAA receptors. Although (2S,2 ´S)-6 and (2S,2 ´S)-7 are comparable to (S)-isoserine with respect to potency, the selectivity vs. the taurine transporter was significantly improved (at least 6 and 53 times more activity at hGAT3, respectively). A subsequent comprehensive structure-activity study showed that different connectivity approaches, stereochemical variations, simple or larger α- andN-substituents, and even minor size enlargement of the het...

Source: Medicinal Chemistry Research - August 16, 2023 Category: Chemistry Source Type: research