Effects of new fluorinated analogues of GABA, pregabalin bioisosters, on the ambient level and exocytotic release of [3H]GABA from rat brain nerve terminals

• Published in: Bioorganic & medicinal chemistry 2017-01, Vol.25 (2), p.759-764
• Main Authors: Borisova, T., Pozdnyakova, N., Shaitanova, E., Gerus, I., Dudarenko, M., Haufe, G., Kukhar, V.
• Format: Article
• Language: English
• Subjects: [3H]GABA release; Ambient level; Animals; Brain - drug effects; Brain - metabolism; Dose-Response Relationship, Drug; Exocytosis - drug effects; Fluorinated analogues of γ-aminobutyric acid (β-polyfluoroalkyl-GABAs); Halogenation; Male; Molecular Structure; Nerve Endings - drug effects; Nerve Endings - metabolism; Pregabalin; Pregabalin - chemical synthesis; Pregabalin - chemistry; Pregabalin - pharmacology; Radiopharmaceuticals - chemical synthesis; Radiopharmaceuticals - chemistry; Radiopharmaceuticals - pharmacology; Rat brain nerve terminals; Rats; Rats, Wistar; Structure-Activity Relationship; Tritium - chemistry
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2016.11.052

[Display omitted] •Properties of new synthesized fluorinated analogues of GABA were analyzed.•The analogues did not influence the ambient level of [3H]GABA in nerve terminals.•The analogues decreased exocytotic release of [3H]GABA from nerve terminals.•Comparative analysis of the effects of the analogues and pregabalin was performed. 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.