Synthesis and biological evaluation of new derivatives of 2-substituted 4-hydroxybutanamides as GABA uptake inhibitors.
This study presents the synthesis of novel substituted 4-hydroxybutanamides and their influence on the activity of murine GABA transport proteins GAT1-GAT4. The active compounds, derivatives of N-arylalkyl-2-(4-diphenylmethylpiperazin-1-yl)-4-hydroxybutyramide, are characterized by pIC(50) values in range of 3.92-5.06 and by slight subtype-selectivity. Among them N-4-chlorobenzylamide was the most potent GAT inhibitor (mGAT3), while N-benzylamide was the most active in GAT1-binding assay (pK(i) = 4.96). The results pointed out that benzhydryl and benzylamide moieties are crucial for the activity of this class of compounds as murine GAT inhibitors.
Department of Physicochemical Drug Analysis, Chair of Pharmaceutical Chemistry, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.
Katarzyna
K
Kulig
Krzysztof
K
Więckowski
Anna
A
Więckowska
Justyna
J
Gajda
Bartłomiej
B
Pochwat
Georg C
GC
Höfner
Klaus T
KT
Wanner
Barbara
B
Malawska
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D000440:Butanols / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D050485:GABA Plasma Membrane Transport Proteins / Q000378:metabolism; D058805:GABA Uptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D051379:Mice; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D000927:Anticonvulsants; D000440:Butanols; D050485:GABA Plasma Membrane Transport Proteins; D058805:GABA Uptake Inhibitors; D005680:gamma-Aminobutyric Acid