PMID- 26138193
OWN - NLM
STAT- MEDLINE
DCOM- 20160517
LR  - 20200721
IS  - 1464-3391 (Electronic)
IS  - 0968-0896 (Linking)
VI  - 23
IP  - 15
DP  - 2015 Aug 1
TI  - Synthesis of new fluorinated analogs of GABA, Pregabalin bioisosteres, and their 
      effects on [(3)H]GABA uptake by rat brain nerve terminals.
PG  - 4316-4323
LID - S0968-0896(15)00532-5 [pii]
LID - 10.1016/j.bmc.2015.06.038 [doi]
AB  - Fluorinated analogs of natural substances take an essential place in the design 
      of new biologically active compounds. New fluorinated analogs of gamma-aminobutyric 
      acid, that is, beta-polyfluoroalkyl-GABAs (FGABAs), were synthesized with 
      substituents: beta-CF3-beta-OH (1), beta-CF3 (2); beta-CF2CF2H (3). FGABAs are bioisosteres 
      of Pregabalin (Lyrica(R), Pfizer's blockbuster drug, beta-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 (100muM) 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.
CI  - Copyright (c) 2015 Elsevier Ltd. All rights reserved.
FAU - Borisova, T
AU  - Borisova T
AD  - The Department of Neurochemistry, Palladin Institute of Biochemistry, NAS of 
      Ukraine, 9 Leontovicha Street, Kiev 01601, Ukraine. Electronic address: 
      tborisov@biochem.kiev.ua.
FAU - Pozdnyakova, N
AU  - Pozdnyakova N
AD  - The Department of Neurochemistry, Palladin Institute of Biochemistry, NAS of 
      Ukraine, 9 Leontovicha Street, Kiev 01601, Ukraine.
FAU - Shaitanova, E
AU  - Shaitanova E
AD  - The Department of Fine Organic Synthesis, Institute of Bioorganic Chemistry and 
      Petrochemistry, NAS of Ukraine, Murmanskaya Str. 1, Kiev 02094, Ukraine.
FAU - Gerus, I
AU  - Gerus I
AD  - The Department of Fine Organic Synthesis, Institute of Bioorganic Chemistry and 
      Petrochemistry, NAS of Ukraine, Murmanskaya Str. 1, Kiev 02094, Ukraine.
FAU - Dudarenko, M
AU  - Dudarenko M
AD  - The Department of Neurochemistry, Palladin Institute of Biochemistry, NAS of 
      Ukraine, 9 Leontovicha Street, Kiev 01601, Ukraine.
FAU - Mironets, R
AU  - Mironets R
AD  - The Department of Fine Organic Synthesis, Institute of Bioorganic Chemistry and 
      Petrochemistry, NAS of Ukraine, Murmanskaya Str. 1, Kiev 02094, Ukraine.
FAU - Haufe, G
AU  - Haufe G
AD  - Organic Chemistry Institute, Corrensstr. 40, D-48149 Munster, Germany.
FAU - Kukhar, V
AU  - Kukhar V
AD  - The Department of Fine Organic Synthesis, Institute of Bioorganic Chemistry and 
      Petrochemistry, NAS of Ukraine, Murmanskaya Str. 1, Kiev 02094, Ukraine.
LA  - eng
PT  - Journal Article
DEP - 20150619
PL  - England
TA  - Bioorg Med Chem
JT  - Bioorganic & medicinal chemistry
JID - 9413298
RN  - 0 (GABA Plasma Membrane Transport Proteins)
RN  - 10028-17-8 (Tritium)
RN  - 284SYP0193 (Fluorine)
RN  - 55JG375S6M (Pregabalin)
RN  - 56-12-2 (gamma-Aminobutyric Acid)
SB  - IM
MH  - Animals
MH  - Brain/*metabolism
MH  - Fluorine/*chemistry
MH  - GABA Plasma Membrane Transport Proteins/chemistry/metabolism
MH  - Male
MH  - Pregabalin/*chemistry/metabolism
MH  - Rats
MH  - Rats, Wistar
MH  - Synaptosomes/metabolism
MH  - Tritium/chemistry
MH  - gamma-Aminobutyric Acid/*analogs & derivatives/chemical synthesis/metabolism
OTO - NOTNLM
OT  - Fluorinated analogs of gamma-aminobutyric acid (beta-polyfluoroalkyl-GABAs)
OT  - Lyrica
OT  - Pregabalin
OT  - Rat brain nerve terminals
OT  - [(3)H]GABA uptake
EDAT- 2015/07/04 06:00
MHDA- 2016/05/18 06:00
CRDT- 2015/07/04 06:00
PHST- 2015/04/08 00:00 [received]
PHST- 2015/06/08 00:00 [revised]
PHST- 2015/06/11 00:00 [accepted]
PHST- 2015/07/04 06:00 [entrez]
PHST- 2015/07/04 06:00 [pubmed]
PHST- 2016/05/18 06:00 [medline]
AID - S0968-0896(15)00532-5 [pii]
AID - 10.1016/j.bmc.2015.06.038 [doi]
PST - ppublish
SO  - Bioorg Med Chem. 2015 Aug 1;23(15):4316-4323. doi: 10.1016/j.bmc.2015.06.038. 
      Epub 2015 Jun 19.