Insight into the Structure of the Neutral Amino Acid Transporter B⁰AT2 Enabled the Discovery of Tiagabine as an Inhibitor

The sodium-dependent membrane transporter SLC6A15 (B⁰AT2) belongs to the SLC6 family, which comprises carriers of amino acids and monoamines. B⁰AT2 is expressed in the central nervous system (CNS), including the glutaminergic and GABAergic system. SLC6A15 supplies neurons with neutral amino acids. Its main substrates, branched-chain amino acids, and proline serve for glutamate biosynthesis, whereas silencing of B⁰AT2 leads to lower levels of neuronal glutamate. Recent research revealed that polymorphisms in the vicinity of <i>slc6a15</i> are associated with major depressive disorder and anxiety. Mouse B⁰AT2 knockouts, by contrast, showed an antianxiety feature. Applying computational tools, we constructed models of B⁰AT2. Their structure was discussed extensively, enabling insight into the determinants of transport mechanism and substrate selectivity. Understanding the molecular basis of the B⁰AT2 inhibition by loratadine led to the discovery of a new inhibitor that is tiagabine, an anticonvulsant drug prescribed off-label in the treatment of anxiety and possessing antidepressant features. The results showed that tiagabine appears to have a higher affinity to the transporter than loratadine, which is the most potent inhibitor to date. Our findings support the development of new B⁰AT2 inhibitors that could be useful for investigating their therapeutic relevance, while the identification of tiagabine as a novel SLC6A15 inhibitor adds a new dimension to the pharmacological complexity of this drug.