Bicyclic γ-amino acids as inhibitors of γ-aminobutyrate aminotransferase

Abstract

The γ-aminobutyrate (GABA)-degradative enzyme GABA aminotransferase (GABA-AT) is regarded as an attractive target to control GABA levels in the central nervous system: this has important implications in the treatment of several neurological disorders and drug dependencies. We have investigated the ability of newly synthesized compounds to act as GABA-AT inhibitors. These compounds have a unique bicyclic structure: the carbocyclic ring bears the GABA skeleton, while the fused 3-Br-isoxazoline ring contains an electrophilic warhead susceptible of nucleophilic attack by an active site residue of the target enzyme. Out of the four compounds tested, only the one named (+)-3 was found to significantly inhibit mammalian GABA-AT in vitro. Docking studies, performed on the available structures of GABA-AT, support the experimental findings: out of the four tested compounds, only (+)-3 suitably orients the electrophilic 3-Br-isoxazoline warhead towards the active site nucleophilic residue Lys329, thereby explaining the irreversible inhibition of GABA-AT observed experimentally.

• 3-Br-isoxazoline
• docking
• GABA
• GABA cyclic analogue
• PLP-dependent enzyme

Acknowledgements

A. C. is grateful to Dr. S. Cosconati for helpful discussion.

Declaration of interests

The authors have declared that no competing interests exist.

Financial support from MIUR to CDM (PRIN 2012) is gratefully acknowledged. DDB thanks Fondazione Roma for partially supporting this work.

Supplementary material available online

Supplementary Figure 1S.