Abstract: 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 slc6a15 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.
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With hydrogenchloride; In 1,4-dioxane; at 20℃; for 2.0h;
(Comparative Example 5) The compound in Comparative Example 5 was synthesized according to the method described in the Patent document 2: ethyl(2S,4S)-1-tert-butoxycarbonyl-4-(phenylsulfanyl)pyrrolidine-2-carboxylate, prepared from ethyl(2S,4R)-1-tert-butoxycarbonyl-4-(4-toluenesulphonyloxy)-pyrrolidine-2-carboxylate and thiophenol, was hydrolyzed with sodium hydroxide and then the product was treated with 4 M hydrochloric acid in dioxane at room temperature for 2 hours to afford the deprotected compound.
With water; sodium hydrogencarbonate; sodium carbonate; In acetone; at 15 - 20℃;pH 8 - 10;Large scale reaction;
General procedure: The (S)-amino acid (10.0 g) was dissolved in H2O (300 ml) and Na2CO3 (2.0 equiv) and NaHCO3 (1.0 equiv) were added at rt, with stirring, to give a clear solution. Acetone (4.0 vol, with respect to the amino acid) was added and the slightly turbid solution was cooled in an ice water bath to 15-20 C. Cbz-Cl (1.25 equiv) was added slowly, with stirring, and the reaction mixture allowed to warm to rt. After stirring for an additional 3 h at rt the mixture was extracted with Et2O (50 ml). To the aqueous phase was slowly added aqueous HCl to give a pH of 2. The resulting oil was extracted into EtOAc (150 ml) and this was washed with H2O (100 ml) and then concentrated in vacuo to give the N-Cbz amino acid as a white solid, see Table 1.
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