title: Synthesis of new fluorinated analogs of GABA, Pregabalin bioisosteres, and their effects on [(3)H]GABA uptake by rat brain nerve terminals.
abstract: Fluorinated analogs of natural substances take an essential place in the design of new biologically active compounds. New fluorinated analogs of γ-aminobutyric acid, that is, β-polyfluoroalkyl-GABAs (FGABAs), were synthesized with substituents: β-CF3-β-OH (1), β-CF3 (2); β-CF2CF2H (3). FGABAs are bioisosteres of Pregabalin (Lyrica®, Pfizer's blockbuster drug, β-i-Bu-GABA), and have lipophilicity close to this medicine. The effects of synthesized FGABAs on [(3)H]GABA uptake by isolated rat brain nerve terminals (synaptosomes) were assessed and compared with those of Pregabalin. FGABAs 1-3 (100μM) did not influence the initial velocity of [(3)H]GABA uptake when applied acutely, whereas an increase in this parameter was found after preliminary incubation of FGABAs with synaptosomes. Pregabalin after preliminary incubation with synaptosomes caused unidirectional changes in the initial velocity of [(3)H]GABA uptake. Using specific inhibitors of GAT1 and GAT3, NO-711 and SNAP5114, respectively, the ability of FGABAs 1-3 to influence non-GAT1 and non-GAT3 uptake activity of nerve terminals was analyzed, but no specificity was found. Therefore, new synthesized FGABAs are structural but not functional analogs of GABA (because they did not inhibit synaptosomal [(3)H]GABA uptake). Moreover, FGABAs are able to increase the initial velocity of [(3)H]GABA uptake by synaptosomes, and this effect is higher than that of Pregabalin.
authors.affiliation: The Department of Neurochemistry, Palladin Institute of Biochemistry, NAS of Ukraine, 9 Leontovicha Street, Kiev 01601, Ukraine. Electronic address: tborisov@biochem.kiev.ua.
authors.forename: T
authors.initials: T
authors.lastname: Borisova
authors.affiliation: The Department of Neurochemistry, Palladin Institute of Biochemistry, NAS of Ukraine, 9 Leontovicha Street, Kiev 01601, Ukraine.
authors.forename: N
authors.initials: N
authors.lastname: Pozdnyakova
authors.affiliation: The Department of Fine Organic Synthesis, Institute of Bioorganic Chemistry and Petrochemistry, NAS of Ukraine, Murmanskaya Str. 1, Kiev 02094, Ukraine.
authors.forename: E
authors.initials: E
authors.lastname: Shaitanova
authors.affiliation: The Department of Fine Organic Synthesis, Institute of Bioorganic Chemistry and Petrochemistry, NAS of Ukraine, Murmanskaya Str. 1, Kiev 02094, Ukraine.
authors.forename: I
authors.initials: I
authors.lastname: Gerus
authors.affiliation: The Department of Neurochemistry, Palladin Institute of Biochemistry, NAS of Ukraine, 9 Leontovicha Street, Kiev 01601, Ukraine.
authors.forename: M
authors.initials: M
authors.lastname: Dudarenko
authors.affiliation: The Department of Fine Organic Synthesis, Institute of Bioorganic Chemistry and Petrochemistry, NAS of Ukraine, Murmanskaya Str. 1, Kiev 02094, Ukraine.
authors.forename: R
authors.initials: R
authors.lastname: Mironets
authors.affiliation: Organic Chemistry Institute, Corrensstr. 40, D-48149 Münster, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Haufe
authors.affiliation: The Department of Fine Organic Synthesis, Institute of Bioorganic Chemistry and Petrochemistry, NAS of Ukraine, Murmanskaya Str. 1, Kiev 02094, Ukraine.
authors.forename: V
authors.initials: V
authors.lastname: Kukhar
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D005461:Fluorine / Q000737:chemistry*; D050485:GABA Plasma Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism; D008297:Male; D000069583:Pregabalin / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013574:Synaptosomes / Q000378:metabolism; D014316:Tritium / Q000737:chemistry; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism
chemical_list: D050485:GABA Plasma Membrane Transport Proteins; D014316:Tritium; D005461:Fluorine; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid
keywords: Fluorinated analogs of γ-aminobutyric acid (β-polyfluoroalkyl-GABAs); Lyrica; Pregabalin; Rat brain nerve terminals; [(3)H]GABA uptake