title: 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.
authors: a Dipartimento di Scienze Farmaceutiche , Università degli Studi di Milano , Milano , Italy .
authors: Andrea
authors: A
authors: Pinto
authors: a Dipartimento di Scienze Farmaceutiche , Università degli Studi di Milano , Milano , Italy .
authors: Lucia
authors: L
authors: Tamborini
authors: b Istituto Pasteur - Fondazione Cenci Bolognetti, Dipartimento di Scienze e Biotecnologie Medico-Chirurgiche, Sapienza Università di Roma , Latina , Italy , and.
authors: Eugenia
authors: E
authors: Pennacchietti
authors: c Istituto Pasteur - Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma , Roma , Italy.
authors: Antonio
authors: A
authors: Coluccia
authors: c Istituto Pasteur - Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma , Roma , Italy.
authors: Romano
authors: R
authors: Silvestri
authors: a Dipartimento di Scienze Farmaceutiche , Università degli Studi di Milano , Milano , Italy .
authors: Gregorio
authors: G
authors: Cullia
authors: a Dipartimento di Scienze Farmaceutiche , Università degli Studi di Milano , Milano , Italy .
authors: Carlo
authors: C
authors: De Micheli
authors: a Dipartimento di Scienze Farmaceutiche , Università degli Studi di Milano , Milano , Italy .
authors: Paola
authors: P
authors: Conti
authors: b Istituto Pasteur - Fondazione Cenci Bolognetti, Dipartimento di Scienze e Biotecnologie Medico-Chirurgiche, Sapienza Università di Roma , Latina , Italy , and.
authors: Daniela
authors: D
authors: De Biase
mesh_terms: D000612:4-Aminobutyrate Transaminase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000596:Amino Acids / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D020134:Catalytic Domain; D060326:Chemistry Techniques, Synthetic; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D004791:Enzyme Inhibitors; D000612:4-Aminobutyrate Transaminase
keywords: 3-Br-isoxazoline; GABA; GABA cyclic analogue; PLP-dependent enzyme; docking