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

Abstract

The g-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.

A New Inhibitor of γ-aminobutric Acid Aminotransferase from Streptomyces sp. ZZ035 Isolated from a Folk Medicinal Soil in China

“…5) according to previous works [16,[19][20][21][24][25][26][27] , and all of them were GABA-AT inhibitors. Among approximately sixty GABA derivatives reported, no 2,3-disubstituted GABA derivatives (Fig.…”

“…As GABA-AT is a key enzyme involved in the GABA metabolic pathways and GABA shunt, the inhibitors of this enzyme can increase the level of GABA, and have a potency to cure some diseases derived from the decrease of GABA. After vigabatrin was used as an irreversible GABA-AT inhibitor to cure epilepsy in clinic [18] , many other GABA analogs were synthesized for the inhibitory evaluation of GABA-AT [16,[19][20][21][22][23][24][25][26][27] . Moreover, gabaculine, a naturally occurring neurotoxin produced by the bacteria Streptomyces toyocaensis No.…”

Inspired by Nature: The 3‐Halo‐4,5‐dihydroisoxazole Moiety as a Novel Molecular Warhead for the Design of Covalent Inhibitors

“…g-Aminobutyrate aminotransferase inhibitors g-Aminobutyrate aminotransferase (GABA-AT), ap yridoxal phosphate (PLP)-dependente nzyme,i sr egarded asa na ttractive target to control GABA levels in the central nervous system,s ince aberration of GABAergic neurotransmission has been implicated in several neurological disorders and drug dependency.B icyclic g-aminoa cid 8 was recently shown to inhibit GABA-ATi natime-and concentration-dependent manner. [28] In vitro experiments, rationalized by docking studies, led us to hypothesize that, while the GABA skeleton incorporatedi nto the carbocyclic structure acts as ar ecognition moiety,w ith the amino group being involved in the formationo fa ni mine with PLP,t he 3-bromo-isoxazoline ring is oriented towards the nucleophilic residueL ys329, and might undergo nucleophilic attack, leadingt oc ovalent bindinga nd irreversible inhibition of the enzyme. [28] ChemMedChem 2016, 11,10-14 www.chemmedchem.org This is the first report of a3bromo-isoxazoline derivative with inhibitory activity against aP LP-dependente nzyme.…”

“…[28] In vitro experiments, rationalized by docking studies, led us to hypothesize that, while the GABA skeleton incorporatedi nto the carbocyclic structure acts as ar ecognition moiety,w ith the amino group being involved in the formationo fa ni mine with PLP,t he 3-bromo-isoxazoline ring is oriented towards the nucleophilic residueL ys329, and might undergo nucleophilic attack, leadingt oc ovalent bindinga nd irreversible inhibition of the enzyme. [28] ChemMedChem 2016, 11,10-14 www.chemmedchem.org This is the first report of a3bromo-isoxazoline derivative with inhibitory activity against aP LP-dependente nzyme. Since some catalytic features are conserved in the active site of most of these enzymes, we hypothesize that the 3bromo-isoxazoline warhead could be efficiently used also to modulate other metabolic pathways in which this class of enzymes are involved.…”

Effects of 3‐Bromo‐4,5‐dihydroisoxazole Derivatives on Nrf2 Activation and Heme Oxygenase‐1 Expression

“…The 3‐halo‐4,5‐dihydroisoxazole warhead can be considered a rare electrophile in therapeutics since it reacts solely with cysteine residues activated by surrounding amino acid residues present in the catalytic site of a number of enzymes. Such a peculiarity has already been used to design efficacious inhibitors of different enzymatic targets, ranging from parasitic and bacterial enzymes to human targets involved in the modulation of neuronal metabolic pathways or in tumor cell metabolism . In this context, we tested different isoxazoline‐based electrophiles (Figure ) to examine their effect on the Nrf2/HO‐1 axis.…”