Abstract
In this study, we report the synthesis and biological evaluation of a variety of α- and β-hydroxy substituted amino acid derivatives as potential amino acid subunits in inhibitors of GABA uptake transporters (GATs). In order to ensure that the test compounds adopt a binding pose similar to that presumed for related larger GAT inhibitors, lipophilic residues were introduced either at the amino nitrogen atom or at the alcohol function. Several of the synthesized compounds were found to exhibit similar inhibitory activity at the GAT subtypes mGAT2, mGAT3, and mGAT4, respectively, as compared with the reference N-butylnipecotic acid. Hence, these compounds might serve as starting point for future developments of more complex GAT inhibitors.
Highlights
Gamma-aminobutyric acid (GABA) is the most abundant inhibitory neurotransmitter in the mammalian central nervous system (CNS) (Bowery and Smart 2006), with up to 40% of synapses estimated to be GABAergic (Meldrum and Chapman 1999)
A promising therapeutical approach for the treatment of these diseases exists in the inhibition of the transport molecules responsible for the removal of GABA from the synaptic cleft, resulting in the prolongation of the effect exerted by the available GABA (Krogsgaard-Larsen et al 1991)
For the synthesis of the cyclic N-butylhydroxyamino acids 11d, 11g, 12g, and 13d we intended to start from the benzyl- or benzhydryl-protected cyclic aminoketones 11a, 12a and 13a, respectively
Summary
Gamma-aminobutyric acid (GABA) is the most abundant inhibitory neurotransmitter in the mammalian central nervous system (CNS) (Bowery and Smart 2006), with up to 40% of synapses estimated to be GABAergic (Meldrum and Chapman 1999). Deficient GABAergic neurotransmission is assumed to play a decisive role in the pathogenesis of several severe neurological diseases, including Alzheimer’s disease (Lanctôt et al 2004), depression (Kalueff and Nutt 2007), epilepsy (Treimann 2001), and neuropathic pain (Daemen et al 2008). A promising therapeutical approach for the treatment of these diseases exists in the inhibition of the transport molecules responsible for the removal of GABA from the synaptic cleft, resulting in the prolongation of the effect exerted by the available GABA (Krogsgaard-Larsen et al 1991).
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