Sevincli, Zekiye SeymaBildirici, NurettinCetin, AdnanBildirici, Ishak2025-05-102025-05-1020232365-654910.1002/slct.2023026832-s2.0-85171326373https://doi.org/10.1002/slct.202302683https://hdl.handle.net/20.500.14720/9634Cetin, Adnan/0000-0003-4838-1503& gamma;-aminobutyric acid (GABA) is the main neuroinhibitory transmitter and a non-proteinogenic amino acid in the brain. When the brain concentration of GABA diminishes below a threshold level, it can cause excess neuronal excitation and lead to convulsions. & gamma;-Aminobutyric acid aminotransferase (GABA-AT) is an enzyme that catalyzes the conversion of GABA to succinic semialdehyde in the GABA shunt pathway and responsible for breaking down GABA in the brain. By inhibiting GABA-AT activity, it may be possible to increase the levels of GABA in the brain and reduce the likelihood of seizures. Herein, the synthesis and evaluation of & alpha;-pyrazolo-(aryl/alkyl)methyl-ketone and pyrazolo[5,1-a]isoquinoline derivatives were carried out anticonvulsant activity, with a focusing on GABA-AT inhibition. In total, 20 novel compounds were synthesized, and characterized with binding assays at GABA-AT receptor, in the 0.060 & PLUSMN;0.01 to 5.99 & PLUSMN;0.10 micromolar range. The ADMET predictions and drug-like characteristics of & alpha;-pyrazolo-(aryl/alkyl)methyl-ketone and pyrazolo[5,1-a]isoquinoline compounds were identified by pharmacokinetic investigations. Furthermore, the predicted analogue-enzyme complexes with docking scores were in the range of -7.3 to -10.5, and their SAR analysis was found to be significant of & alpha;-pyrazolo-(aryl/alkyl)methyl-ketone and pyrazolo[5,1-a]isoquinoline structures in medicinal chemistry. Our results revealed that this new structural information will be useful for the future design and synthesis of activity-based GABA-AT inhibitors. The research presented in this manuscript is focused on the development of new high affinity ligands for GABA-AT receptor. These analogues for GABA-AT inhibitor candidates were designed using the scaffold from the pyrazole and isoquinoline by omitting the substituent in the 3,5-positions. The pharmacological profile of these analogues was determined using an in vitro method. This has aided in the design of a novel selective inhibitor for the GABA-AT receptor.imageeninfo:eu-repo/semantics/openAccessAdmetAntioxidantsDrug DiscoveryEnzymesPharmacokineticsArticle835Q3Q3WOS:001065927400001