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1.
Bioorg Med Chem ; 25(2): 759-764, 2017 01 15.
Article in English | MEDLINE | ID: mdl-27956036

ABSTRACT

Recently, we have shown that new fluorinated analogues of γ-aminobutyric acid (GABA), bioisosters of pregabalin (ß-i-Bu-GABA), i.e. ß-polyfluoroalkyl-GABAs (FGABAs), with substituents: ß-CF3-ß-OH (1), ß-CF3 (2); ß-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.


Subject(s)
Brain/drug effects , Nerve Endings/drug effects , Pregabalin/pharmacology , Radiopharmaceuticals/pharmacology , Tritium/chemistry , Animals , Brain/metabolism , Dose-Response Relationship, Drug , Exocytosis/drug effects , Halogenation , Male , Molecular Structure , Nerve Endings/metabolism , Pregabalin/chemical synthesis , Pregabalin/chemistry , Radiopharmaceuticals/chemical synthesis , Radiopharmaceuticals/chemistry , Rats , Rats, Wistar , Structure-Activity Relationship
2.
Bioorg Med Chem ; 23(15): 4316-4323, 2015 Aug 01.
Article in English | MEDLINE | ID: mdl-26138193

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, ß-polyfluoroalkyl-GABAs (FGABAs), were synthesized with substituents: ß-CF3-ß-OH (1), ß-CF3 (2); ß-CF2CF2H (3). FGABAs are bioisosteres of Pregabalin (Lyrica®, Pfizer's blockbuster drug, ß-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.


Subject(s)
Brain/metabolism , Fluorine/chemistry , Pregabalin/chemistry , gamma-Aminobutyric Acid/analogs & derivatives , Animals , GABA Plasma Membrane Transport Proteins/chemistry , GABA Plasma Membrane Transport Proteins/metabolism , Male , Pregabalin/metabolism , Rats , Rats, Wistar , Synaptosomes/metabolism , Tritium/chemistry , gamma-Aminobutyric Acid/chemical synthesis , gamma-Aminobutyric Acid/metabolism
3.
J Antibiot (Tokyo) ; 51(5): 499-507, 1998 May.
Article in English | MEDLINE | ID: mdl-9666179

ABSTRACT

Two pyoverdin-ampicillin conjugates were synthesized and their structures were confirmed by mass spectrometry and NMR spectroscopy. In contrast to ampicillin, the conjugates exhibited high antibacterial activity against Pseudomonas aeruginosa ATCC 15692 and ATCC 27853, effective only against the strain which is using the parent pyoverdin for iron uptake. This suggests that the conjugates enter the bacterial cell via the ferripyoverdin uptake pathway. Growth stimulation studies with conjugates hydrolysed at the beta-lactam ring of the ampicillin moiety supported this view.


Subject(s)
Ampicillin/chemical synthesis , Ampicillin/metabolism , Oligopeptides , Pigments, Biological/chemical synthesis , Pigments, Biological/metabolism , Pseudomonas aeruginosa/metabolism , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/metabolism , Anti-Bacterial Agents/pharmacology , Iron/metabolism , Iron Chelating Agents/chemical synthesis , Iron Chelating Agents/chemistry , Iron Chelating Agents/metabolism , Magnetic Resonance Spectroscopy , Mass Spectrometry , Microbial Sensitivity Tests , Molecular Structure , Pigments, Biological/chemistry , Siderophores/chemical synthesis , Siderophores/chemistry , Siderophores/metabolism
4.
Amino Acids ; 4(3): 303-6, 1993 Oct.
Article in English | MEDLINE | ID: mdl-24190610

ABSTRACT

3-Fluorotyrosine fluorescence is quenched effectively by phosphate ions not only by a dynamic but also by a static mechanism owing to H-bond complex formation in ground state. 3-Fluorotyrosine pKa values both in the ground and first excited state (8.3 and 4, respectively) are appreciably lower than those of tyrosine, thus promoting 3-fluorotyrosinate ion formation in the excited state. Additional emission owing to 3-fluorotyrosinate ion (near 350 nm) may be taken erroneously for tryptophan fluorescence.

5.
Amino Acids ; 5(1): 99-101, 1993 Feb.
Article in English | MEDLINE | ID: mdl-24190648

ABSTRACT

Racemic N-Boc-4-difluoromethoxyphenylglycine was prepared by O-difluoromethylation of D-N-Boc-4-hydroxyphenylglycine under basic conditions, whereas the hexafluoropropylation reaction gives optically pure D-N-Boc-4-hexafluoropropoxyphenylglycine. D,L-4-difluoromethoxyphenylglycine was obtained by the action of TFA on the corresponding amino acid derivative.

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