title: Synthesis of N-substituted acyclic β-amino acids and their investigation as GABA uptake inhibitors.
abstract: 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 pIC50 value of 5.34 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.
authors.affiliation: Department Pharmazie, Zentrum für Pharmaforschung, LMU München, Butenandtstr. 5-13, D-81377 München, Germany.
authors.forename: Ingolf
authors.initials: I
authors.lastname: Sitka
authors.forename: Lars
authors.initials: L
authors.lastname: Allmendinger
authors.forename: Günther
authors.initials: G
authors.lastname: Fülep
authors.forename: Georg
authors.initials: G
authors.lastname: Höfner
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Wanner
mesh_terms: D000596:Amino Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000378:metabolism; D050485:GABA Plasma Membrane Transport Proteins / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D015394:Molecular Structure; D013552:Swine
chemical_list: D000596:Amino Acids; D050485:GABA Plasma Membrane Transport Proteins
keywords: Antiepileptic; BGT1; GABA uptake inhibitors; GAT1; GAT2; GAT3; Mitsunobu reaction; β-amino acids