title: Effects of new fluorinated analogues of GABA, pregabalin bioisosters, on the ambient level and exocytotic release of [3H]GABA from rat brain nerve terminals.
abstract: Recently, we have shown that new fluorinated analogues of γ-aminobutyric acid (GABA), bioisosters of pregabalin (β-i-Bu-GABA), i.e. β-polyfluoroalkyl-GABAs (FGABAs), with substituents: β-CF3-β-OH (1), β-CF3(2); β-CF2CF2H (3), are able to increase the initial rate of [3H]GABA uptake by isolated rat brain nerve terminals (synaptosomes), and this effect is higher than that of pregabalin. So, synthesized FGABAs are structural but not functional analogues of GABA. Herein, we assessed the effects of synthesized FGABAs (100μM) on the ambient level and exocytotic release of [3H]GABA in nerve terminals and compared with those of pregabalin (100μM). It was shown that FGABAs 1-3 did not influence the ambient level of [3H]GABA in the synaptosomal preparations, and this parameter was also not altered by pregabalin. During blockage of GABA transporters GAT1 by specific inhibitor NO-711, FGABAs and pregabalin also did not change ambient [3H]GABA in synaptosomal preparations. Exocytotic release of [3H]GABA from synaptosomes decreased in the presence of FGABAs 1-3 and pregabalin, and the effects of FGABAs 1 &3 were more significant than those of FGABAs 2 and pregabalin. FGABAs 1-3/pregabalin-induced decrease in exocytotic release of [3H]GABA from synaptosomes was not a result of changes in the potential of the plasma membrane. Therefore, new synthesized FGABAs 1 &3 were able to decrease exocytotic release of [3H]GABA from nerve terminals more effectively in comparison to pregabalin. Absence of unspecific side effects of FGABAs 1 &3 on the membrane potential makes these compounds perspective for medical application.
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. Electronic address: natapoz@biochem.kiev.ua.
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 Street. 1, Kiev 02094, Ukraine. Electronic address: shaitanova@ukr.net.
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 Street. 1, Kiev 02094, Ukraine. Electronic address: igerus@hotmail.com.
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. Electronic address: marina.dudarenko@gmail.com.
authors.forename: M
authors.initials: M
authors.lastname: Dudarenko
authors.affiliation: Organic Chemistry Institute, Corrensstr. 40, D-48149 Münster, Germany. Electronic address: haufe@uni-muenster.de.
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 Street. 1, Kiev 02094, Ukraine. Electronic address: Kukhar@ibpc.kiev.ua.
authors.forename: V
authors.initials: V
authors.lastname: Kukhar
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005089:Exocytosis / Q000187:drug effects; D054879:Halogenation; D008297:Male; D015394:Molecular Structure; D009411:Nerve Endings / Q000187:drug effects* / Q000378:metabolism; D000069583:Pregabalin / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014316:Tritium / Q000737:chemistry*
chemical_list: D019275:Radiopharmaceuticals; D014316:Tritium; D000069583:Pregabalin
keywords: Ambient level; Fluorinated analogues of γ-aminobutyric acid (β-polyfluoroalkyl-GABAs); Pregabalin; Rat brain nerve terminals; [(3)H]GABA release