Synthesis of N-substituted acyclic β-amino acids and their investigation as GABA uptake inhibitors

In this publication, we describe the synthesis of new inhibitors for the GABA transporter subtypes GAT1 and especially GAT3. We started with 3-aminopropanoic acid possessing a distinct preference for GAT3 in comparison to GAT1 and furthermore its homolog 3-aminobutanoic acid. A series of respective N-substituted amino acids was synthesized by selective N-monoalkylation of these parent structures with 6 different arylalkyl alcohols via a Mitsunobu-type reaction. The resulting compounds were investigated for their inhibitory potency GABA transporter subtypes. Among all tested compounds the 4,4-diphenylbut-3-enyl substituted 3-aminobutanoic acid (rac)-6b showed highest potency with a pIC(50) value of 534 at GAT1 Unfortunately, the expected GAT3 potency for 2-[tris(4-methoxyphenyl)methoxy] ethyl substituted derivatives was not as high as observed for the respective nipecotic acid derivatives. (C) 2013 Elsevier Masson SAS. All rights reserved.