Generic placeholder image

Current Medicinal Chemistry


ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Review Article

Development, Recent Achievements and Current Directions of Research into GABA Uptake Inhibitors

Author(s): Paula Zaręba, Beata Gryzło, Gabriela Mazur and Barbara Malawska*

Volume 28, Issue 4, 2021

Published on: 10 October, 2019

Page: [750 - 776] Pages: 27

DOI: 10.2174/0929867325666191010120236

Price: $65


Neurotransmitter γ-aminobutyric acid (GABA) plays a principal role in the regulation of mammalian central nervous system functions. GABA evoked neurotransmission is terminated by a rapid uptake via dependent plasma membrane GABA transporters (GATs) located in the cell membrane. Potent inhibitors of these GATs are of fundamental importance for elucidation of the physiological function of these targets. Over recent years, a wide range of new GAT1-selective and less common non-GAT1-selective inhibitors have been successfully developed. This review highlights development and recent significant achievements in the field of GABA reuptake inhibitors. Special attention is paid to their pharmacological roles, structure and subtype selectivity relationships.

Keywords: GABA transporters, GAT1, BGT1, GAT2, GAT3, GABA uptake inhibitors.

Lydiard, R.B. The role of GABA in anxiety disorders. J. Clin. Psychiatry, 2003, 64(Suppl. 3), 21-27.
[PMID: 12662130]
Gong, X.; Shao, Y.; Li, B.; Chen, L.; Wang, C.; Chen, Y. γ-aminobutyric acid transporter-1 is involved in anxiety-like behaviors and cognitive function in knockout mice. Exp. Ther. Med., 2015, 10(2), 653-658.
[] [PMID: 26622370]
Sałat, K.; Podkowa, A.; Kowalczyk, P.; Kulig, K.; Dziubina, A.; Filipek, B.; Librowski, T. Anticonvulsant active inhibitor of GABA transporter subtype 1, tiagabine, with activity in mouse models of anxiety, pain and depression. Pharmacol. Rep., 2015, 67(3), 465-472.
[] [PMID: 25933955]
Fijałkowski, Ł.; Sałat, K.; Podkowa, A.; Zaręba, P.; Nowaczyk, A. Potential role of selected antiepileptics used in neuropathic pain as human GABA transporter isoform 1 (GAT1) inhibitors-Molecular docking and pharmaco-dynamic studies. Eur. J. Pharm. Sci., 2017, 96, 362-372.
[] [PMID: 27721044]
Pehrson, A.L.; Sanchez, C. Altered γ-aminobutyric acid neurotransmission in major depressive disorder: a critical review of the supporting evidence and the influence of serotonergic antidepressants. Drug Des. Devel. Ther., 2015, 9, 603-624.
[] [PMID: 25653499]
Pozdnyakova, N.; Dudarenko, M.; Yatsenko, L.; Himmelreich, N.; Krupko, O.; Borisova, T. Perinatal hypoxia: different effects of the inhibitors of GABA transporters GAT1 and GAT3 on the initial velocity of [3H]GABA uptake by cortical, hippocampal, and thalamic nerve terminals. Croat. Med. J., 2014, 55(3), 250-258.
[] [PMID: 24891283]
Bhat, R.; Axtell, R.; Mitra, A.; Miranda, M.; Lock, C.; Tsien, R.W.; Steinman, L. Inhibitory role for GABA in autoimmune inflammation. Proc. Natl. Acad. Sci. USA, 2010, 107(6), 2580-2585.
[] [PMID: 20133656]
Wang, Y.; Feng, D.; Liu, G.; Luo, Q.; Xu, Y.; Lin, S.; Fei, J.; Xu, L. γ-aminobutyric acid transporter 1 negatively regulates T cell-mediated immune responses and ameliorates autoimmune inflammation in the CNS. J. Immunol., 2008, 181(12), 8226-8236.
[] [PMID: 19050239]
Moldavan, M.; Cravetchi, O.; Williams, M.; Irwin, R.P.; Aicher, S.A.; Allen, C.N. Localization and expression of GABA transporters in the suprachiasmatic nucleus. Eur. J. Neurosci., 2015, 42(12), 3018-3032.
[] [PMID: 26390912]
Zarrindast, M.R.; Noorbakhshnia, M.; Motamedi, F.; Haeri-Rohani, A.; Rezayof, A. Effect of the GABAergic system on memory formation and state-dependent learning induced by morphine in rats. Pharmacology, 2006, 76(2), 93-100.
[] [PMID: 16319519]
Zhou, Y.; Danbolt, N.C. GABA and glutamate transporters in brain. Front. Endocrinol. (Lausanne), 2013, 4, 165.
[] [PMID: 24273530]
Rudnick, G.; Krämer, R.; Blakely, R.D.; Murphy, D.L.; Verrey, F. The SLC6 transporters: perspectives on structure, functions, regulation, and models for transporter dysfunction. Pflugers Arch., 2014, 466(1), 25-42.
[] [PMID: 24337881]
Kristensen, A.S.; Andersen, J.; Jørgensen, T.N.; Sørensen, L.; Eriksen, J.; Loland, C.J.; Strømgaard, K.; Gether, U. SLC6 neurotransmitter transporters: structure, function, and regulation. Pharmacol. Rev., 2011, 63(3), 585-640.
[] [PMID: 21752877]
Kempson, S.A.; Zhou, Y.; Danbolt, N.C. The betaine/GABA transporter and betaine: roles in brain, kidney and liver. Front. Physiol., 2014, 5, 159.
[] [PMID: 24795654]
Loo, D.D.F.; Eskandari, S.; Boorer, K.J.; Sarkar, H.K.; Wright, E.M. Role of Cl- in electrogenic Na+-coupled cotransporters GAT1 and SGLT1. J. Biol. Chem., 2000, 275(48), 37414-37422.
[] [PMID: 10973981]
Wu, Y.; Wang, W.; Díez-Sampedro, A.; Richerson, G.B. Nonvesicular inhibitory neurotransmission via reversal of the GABA transporter GAT-1. Neuron, 2007, 56(5), 851-865.
[] [PMID: 18054861]
Gadea, A.; López-Colomé, A.M. Glial transporters for glutamate, glycine and GABA: II. GABA transporters. J. Neurosci. Res., 2001, 63(6), 461-468.
[] [PMID: 11241581]
Willford, S.L.; Anderson, C.M.; Spencer, S.R.; Eskandari, S. Evidence for a revised ion/substrate coupling stoichiometry of GABA transporters. J. Membr. Biol., 2015, 248(4), 795-810.
[] [PMID: 25824654]
Zhou, Y.; Holmseth, S.; Guo, C.; Hassel, B.; Höfner, G.; Huitfeldt, H.S.; Wanner, K.T.; Danbolt, N.C. Deletion of the γ-aminobutyric acid transporter 2 (GAT2 and SLC6A13) gene in mice leads to changes in liver and brain taurine contents. J. Biol. Chem., 2012, 287(42), 35733-35746.
[] [PMID: 22896705]
Jørgensen, L.; Al-Khawaja, A.; Kickinger, S.; Vogensen, S.B.; Skovgaard-Petersen, J.; Rosenthal, E.; Borkar, N.; Löffler, R.; Madsen, K.K.; Bräuner-Osborne, H.; Schousboe, A.; Ecker, G.F.; Wellendorph, P.; Clausen, R.P. Structure-activity relationship, pharmacological characteri-zation, and molecular modeling of noncompetitive inhibitors of the betaine/γ-aminobutyric acid transporter 1 (BGT1). J. Med. Chem., 2017, 60(21), 8834-8846.
[] [PMID: 28991462]
Alexander, S.P.H.; Davenport, A.P.; Kelly, E.; Marrion, N.; Peters, J.A.; Benson, H.E.; Faccenda, E.; Pawson, A.J.; Sharman, J.L.; Southan, C.; Davies, J.A. G protein-coupled receptors. Br. J. Pharmacol., 2015, 172(24), 5744-5869.
[] [PMID: 26650439]
Zafar, S.; Jabeen, I. Structure, function and modulation of γ-aminobutyric acid transporter 1 (GAT1) in neurological disorders: a pharmacoinformatic prospective. Front Chem., 2018, 6, 397.
[] [PMID: 30255012]
Scimemi, A. Structure, function, and plasticity of GABA transporters. Front. Cell. Neurosci., 2014, 8, 161.
[] [PMID: 24987330]
Jasmin, L.; Wu, M.V.; Ohara, P.T. GABA puts a stop to pain. Curr. Drug Targets CNS Neurol. Disord., 2004, 3(6), 487-505.
[] [PMID: 15578966]
Kickinger, S.; Hellsberg, E.; Frølund, B.; Schousboe, A.; Ecker, G.F.; Wellendorph, P. Structural and molecular aspects of betaine-GABA transporter 1 (BGT1) and its relation to brain function. Neuropharmacology 2019, S0028-3908(19), 30170-30174.
Madsen, K.K.; Hansen, G.H.; Danielsen, E.M.; Schousboe, A. The subcellular localization of GABA transporters and its implication for seizure management. Neurochem. Res., 2015, 40(2), 410-419.
[] [PMID: 25519681]
Masuda, N.; Peng, Q.; Li, Q.; Jiang, M.; Liang, Y.; Wang, X.; Zhao, M.; Wang, W.; Ross, C.A.; Duan, W. Tiagabine is neuroprotective in the N171-82Q and R6/2 mouse models of Huntington’s disease. Neurobiol. Dis., 2008, 30(3), 293-302.
[] [PMID: 18395459]
Liu, J.; Huang, D.; Xu, J.; Tong, J.; Wang, Z.; Huang, L.; Yang, Y.; Bai, X.; Wang, P.; Suo, H.; Ma, Y.; Yu, M.; Fei, J.; Huang, F. Tiagabine protects dopaminergic neurons against neurotoxins by inhibiting microglial activation. Sci. Rep., 2015, 5, 15720.
[] [PMID: 26499517]
Sałat, K.; Podkowa, A.; Malikowska, N.; Kern, F.; Pabel, J.; Wojcieszak, E.; Kulig, K.; Wanner, K.T.; Strach, B.; Wyska, E. Novel, highly potent and in vivo active inhibitor of GABA transporter subtype 1 with anticonvulsant, anxiolytic, antidepressant and antinociceptive properties. Neuropharmacology,, 2017, 113(Pt A), 331-342.
[] [PMID: 27771379]
Kern, F.T.; Wanner, K.T. Generation and screening of oxime libraries addressing the neuronal GABA transporter GAT1. ChemMedChem, 2015, 10(2), 396-410.
[] [PMID: 25369775]
Kataoka, K.; Hara, K.; Haranishi, Y.; Terada, T.; Sata, T. The antinociceptive effect of SNAP5114, a gamma-amino-butyric acid transporter-3 inhibitor, in rat experimental pain models. Anesth. Analg., 2013, 116(5), 1162-1169.
[] [PMID: 23456665]
Dhar, T.G.M.; Borden, L.A.; Tyagarajan, S.; Smith, K.E.; Branchek, T.A.; Weinshank, R.L.; Gluchowski, C. Design, synthesis and evaluation of substituted triarylnipecotic acid derivatives as GABA uptake inhibitors: identification of a ligand with moderate affinity and selectivity for the cloned human GABA transporter GAT-3. J. Med. Chem., 1994, 37(15), 2334-2342.
[] [PMID: 8057281]
Borden, L.A. GABA transporter heterogeneity: pharma-cology and cellular localization. Neurochem. Int., 1996, 29(4), 335-356.
[] [PMID: 8939442]
Kvist, T.; Christiansen, B.; Jensen, A.A.; Bräuner-Osborne, H. The four human gamma-aminobutyric acid (GABA) transporters: pharmacological characterization and validation of a highly efficient screening assay. Comb. Chem. High Throughput Screen., 2009, 12(3), 241-249.
[] [PMID: 19275529]
Madsen, K.K.; Clausen, R.P.; Larsson, O.M.; Krogsgaard-Larsen, P.; Schousboe, A.; White, H.S. Synaptic and extra-synaptic GABA transporters as targets for anti-epileptic drugs. J. Neurochem., 2009, 109(Suppl. 1), 139-144.
[] [PMID: 19393020]
Pabel, J.; Faust, M.; Prehn, C.; Wörlein, B.; Allmendinger, L.; Höfner, G.; Wanner, K.T. Development of an (S)-1-2-[tris(4-methoxyphenyl)methoxy]ethylpiperidine-3-carboxylic acid [(S)-SNAP-5114] carba analogue inhibitor for murine γ-aminobutyric acid transporter type 4. ChemMedChem, 2012, 7(7), 1245-1255.
[] [PMID: 22544452]
Lie, M.E.K.; Gowing, E.K.; Johansen, N.B.; Dalby, N.O.; Thiesen, L.; Wellendorph, P.; Clarkson, A.N. GAT3 selective substrate l-isoserine upregulates GAT3 expression and increases functional recovery after a focal ischemic stroke in mice. J. Cereb. Blood Flow Metab., 2019, 39(1), 74-88.
[] [PMID: 29160736]
Schousboe, A.; Madsen, K.K.; Barker-Haliski, M.L.; White, H.S. The GABA synapse as a target for antiepileptic drugs: a historical overview focused on GABA trans-porters. Neurochem. Res., 2014, 39(10), 1980-1987.
[] [PMID: 24627365]
Schousboe, A.; Wellendorph, P.; Frølund, B.; Clausen, R.P.; Krogsgaard-Larsen, P. Astrocytic GABA trans-porters: pharmacological properties and targets for antiepileptic drugs. Adv. Neurobiol., 2017, 16, 283-296.
[] [PMID: 28828616]
Clausen, R.P.; Frølund, B.; Larsson, O.M.; Schousboe, A.; Krogsgaard-Larsen, P.; White, H.S. A novel selective γ-aminobutyric acid transport inhibitor demonstrates a functional role for GABA transporter subtype GAT2/BGT-1 in the CNS. Neurochem. Int., 2006, 48(6-7), 637-642.
[] [PMID: 16517017]
Vogensen, S.B.; Jørgensen, L.; Madsen, K.K.; Borkar, N.; Wellendorph, P.; Skovgaard-Petersen, J.; Schousboe, A.; White, H.S.; Krogsgaard-Larsen, P.; Clausen, R.P. Selective mGAT2 (BGT-1) GABA uptake inhibitors: design, synthesis, and pharmacological characterization. J. Med. Chem., 2013, 56(5), 2160-2164.
[] [PMID: 23398473]
Nakada, K.; Yoshikawa, M.; Ide, S.; Suemasa, A.; Kawamura, S.; Kobayashi, T.; Masuda, E.; Ito, Y.; Hayakawa, W.; Katayama, T.; Yamada, S.; Arisawa, M.; Minami, M.; Shuto, S. Cyclopropane-based conformational restriction of GABA by a stereochemical diversity-oriented strategy: identification of an efficient lead for potent inhibitors of GABA transports. Bioorg. Med. Chem., 2013, 21(17), 4938-4950.
[] [PMID: 23886812]
Kowalczyk, P.; Sałat, K.; Höfner, G.C.; Guzior, N.; Filipek, B.; Wanner, K.T.; Kulig, K. 2-Substituted 4-hydroxybutanamides as potential inhibitors of γ-amino-butyric acid transporters mGAT1-mGAT4: synthesis and biological evaluation. Bioorg. Med. Chem., 2013, 21(17), 5154-5167.
[] [PMID: 23859778]
Sałat, K.; Kulig, K.; Gajda, J.; Więckowski, K.; Filipek, B.; Malawska, B. Evaluation of anxiolytic-like, anticonvulsant, antidepressant-like and antinociceptive properties of new 2-substituted 4-hydroxybutanamides with affinity for GABA transporters in mice. Pharmacol. Biochem. Behav., 2013, 110, 145-153.
[] [PMID: 23850524]
Sarup, A.; Larsson, O.M.; Schousboe, A. GABA transporters and GABA-transaminase as drug targets. Curr. Drug Targets CNS Neurol. Disord., 2003, 2(4), 269-277.
[] [PMID: 12871037]
Damgaard, M.; Al-Khawaja, A.; Vogensen, S.B.; Jurik, A.; Sijm, M.; Lie, M.E.K.; Bæk, M.I.; Rosenthal, E.; Jensen, A.A.; Ecker, G.F.; Frølund, B.; Wellendorph, P.; Clausen, R.P. Identification of the first highly subtype-selective inhibitor of human GABA transporter GAT3. ACS Chem. Neurosci., 2015, 6(9), 1591-1599.
[] [PMID: 26154082]
Petrera, M.; Wein, T.; Allmendinger, L.; Sindelar, M.; Pabel, J.; Höfner, G.; Wanner, K.T. Development of highly potent GAT1 inhibitors: synthesis of nipecotic acid derivatives by suzuki-miyaura cross-coupling reactions. ChemMedChem, 2016, 11(5), 519-538.
[] [PMID: 26683881]
Kragler, A.; Höfner, G.; Wanner, K.T. Synthesis and biological evaluation of aminomethylphenol derivatives as inhibitors of the murine GABA transporters mGAT1-mGAT4. Eur. J. Med. Chem., 2008, 43(11), 2404-2411.
[] [PMID: 18395300]
Høg, S.; Greenwood, J.R.; Madsen, K.B.; Larsson, O.M.; Frølund, B.; Schousboe, A.; Krogsgaard-Larsen, P.; Clausen, R.P. Structure-activity relationships of selective GABA uptake inhibitors. Curr. Top. Med. Chem., 2006, 6(17), 1861-1882.
[] [PMID: 17017962]
Kobayashi, T.; Suemasa, A.; Igawa, A.; Ide, S.; Fukuda, H.; Abe, H.; Arisawa, M.; Minami, M.; Shuto, S. Confor-mationally restricted GABA with Bicyclo[3.1.0]hexane backbone as the first highly selective BGT-1 inhibitor. ACS Med. Chem. Lett., 2014, 5(8), 889-893.
[] [PMID: 25147609]
Yamashita, A.; Singh, S.K.; Kawate, T.; Jin, Y.; Gouaux, E. Crystal structure of a bacterial homologue of Na+/Cl--dependent neurotransmitter transporters. Nature, 2005, 437(7056), 215-223.
[] [PMID: 16041361]
Penmatsa, A.; Wang, K.H.; Gouaux, E. X-Ray structure of the dopamine transporter in complex with tricyclic antidepressant. Nature, 2013, 503(7474), 85-90.
[] [PMID: 24037379]
Coleman, J.A.; Green, E.M.; Gouaux, E. X-ray structures and mechanism of the human serotonin transporter. Nature, 2016, 532(7599), 334-339.
[] [PMID: 27049939]
Damgaard, M.; Haugaard, A.S.; Kickinger, S.; Al-khawaja, A.; Lie, M.E.K.; Ecker, G.F. Development of non-GAT1-selective inhibitors: challenges and achievements. Glial Amino Acid Transporters., 2017, 16, 315-332.
Vogensen, S.B.; Jørgensen, L.; Madsen, K.K.; Jurik, A.; Borkar, N.; Rosatelli, E.; Nielsen, B.; Ecker, G.F.; Schousboe, A.; Clausen, R.P. Structure activity relationship of selective GABA uptake inhibitors. Bioorg. Med. Chem., 2015, 23(10), 2480-2488.
[] [PMID: 25882526]
Wein, T.; Petrera, M.; Allmendinger, L.; Höfner, G.; Pabel, J.; Wanner, K.T. Different binding modes of small and large binders of GAT1. ChemMedChem, 2016, 11(5), 509-518.
[] [PMID: 26804464]
Quick, M.; Shi, L.; Zehnpfennig, B.; Weinstein, H.; Javitch, J.A. Experimental conditions can obscure the second high-affinity site in LeuT. Nat. Struct. Mol. Biol., 2012, 19(2), 207-211.
[] [PMID: 22245968]
Baglo, Y.; Gabrielsen, M.; Sylte, I.; Gederaas, O.A. Homology modeling of human γ-butyric acid transporters and the binding of pro-drugs 5-aminolevulinic acid and methyl aminolevulinic acid used in photodynamic therapy. PLoS One, 2013, 8(6)e65200
[] [PMID: 23762315]
Zafar, S.; Nguyen, M.E.; Muthyala, R.; Jabeen, I.; Sham, Y.Y. Modeling and simulation of hGAT1: a mechanistic investigation of the GABA transport process. Comput. Struct. Biotechnol. J., 2018, 17, 61-69.
[] [PMID: 30619541]
Hediger, M.A.; Romero, M.F.; Peng, J. Bin; Rolfs, A.; Takanaga, H.; Bruford, E. A. The ABCs of solute carriers: physiological, pathological and therapeutic implications of human membrane transport proteins. Pflugers Arch., 2004, 447(5), 465-468.
[] [PMID: 14624363]
Zafar, S.; Jabeen, I. GRID-independent molecular descriptor analysis and molecular docking studies to mimic the binding hypothesis of γ-aminobutyric acid transporter 1 (GAT1) inhibitors. PeerJ, 2019, 7e6283
[] [PMID: 30723616]
Seth, A.; Sharma, P.A.; Tripathi, A.; Choubey, P.K.; Srivastava, P.; Tripathi, P.N.; Shrivastava, S.K. Design, synthesis, evaluation and molecular modeling studies of some novel N-substituted piperidine-3-carboxylic acid derivatives as potential anticonvulsants. Med. Chem. Res., 2018, 27(4), 1206-1225.
Singh, R.B.; Singh, G.K.; Chaturvedi, K.; Kumar, D.; Singh, S.K.; Zaman, M.K. Design, synthesis, characteri-zation, and molecular modeling studies of novel oxadiazole derivatives of nipecotic acid as potential anticonvulsant and antidepressant agents. Med. Chem. Res., 2018, 27(1), 137-152.
Ali, F.E.; Bondinell, W.E.; Dandridge, P.A.; Frazee, J.S.; Garvey, E.; Girard, G.R.; Kaiser, C.; Ku, T.W.; Lafferty, J.J.; Moonsammy, G.I. Orally active and potent inhibitors of gamma-aminobutyric acid uptake. J. Med. Chem., 1985, 28(5), 653-660.
[] [PMID: 2985785]
Andersen, K.E.; Braestrup, C.; Grønwald, F.C.; Jørgensen, A.S.; Nielsen, E.B.; Sonnewald, U.; Sørensen, P.O.; Suzdak, P.D.; Knutsen, L.J. The synthesis of novel GABA uptake inhibitors. 1. Elucidation of the structure-activity studies leading to the choice of (R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylic acid (tiagabine) as an anticonvulsant drug candidate. J. Med. Chem., 1993, 36(12), 1716-1725.
[] [PMID: 8510100]
Knutsen, L.J.S.; Andersen, K.E.; Lau, J.; Lundt, B.F.; Henry, R.F.; Morton, H.E.; Naerum, L.; Petersen, H.; Stephensen, H.; Suzdak, P.D.; Swedberg, M.D.; Thomsen, C.; Sørensen, P.O. Synthesis of novel GABA uptake inhibitors. 3. Diaryloxime and diarylvinyl ether derivatives of nipecotic acid and guvacine as anticonvulsant agents. J. Med. Chem., 1999, 42(18), 3447-3462.
[] [PMID: 10479278]
Andersen, K.E.; Sørensen, J.L.; Huusfeldt, P.O.; Knutsen, L.J.S.; Lau, J.; Lundt, B.F.; Petersen, H.; Suzdak, P.D.; Swedberg, M.D.B. Synthesis of novel GABA uptake inhibitors. 4. Bioisosteric transformation and successive optimization of known GABA uptake inhibitors leading to a series of potent anticonvulsant drug candidates. J. Med. Chem., 1999, 42(21), 4281-4291.
[] [PMID: 10543872]
Carroll, F.I.; Mascarella, S.W.; Kuzemko, M.A.; Gao, Y.; Abraham, P.; Lewin, A.H.; Boja, J.W.; Kuhar, M.J. Synthesis, ligand binding, and QSAR (CoMFA and classical) study of 3 beta-(3′-substituted phenyl)-, 3 beta-(4′-substituted phenyl)-, and 3 beta-(3′,4′-disubstituted phenyl)tropane-2 beta-carboxylic acid methyl esters. J. Med. Chem., 1994, 37(18), 2865-2873.
[] [PMID: 8071935]
Borden, L.A.; Smith, K.E.; Vaysse, P.J.; Gustafson, E.L.; Weinshank, R.L.; Branchek, T.A. Re-evaluation of GABA transport in neuronal and glial cell cultures: correlation of pharmacology and mRNA localization. Receptors Channels, 1995, 3(2), 129-146.
[PMID: 8581400]
Schousboe, A.; Thorbek, P.; Hertz, L.; Krogsgaard-Larsen, P. Effects of GABA analogues of restricted conformation on GABA transport in astrocytes and brain cortex slices and on GABA receptor binding. J. Neurochem., 1979, 33(1), 181-189.
[] [PMID: 458448]
Madsen, K.K.; White, H.S.; Schousboe, A. Neuronal and non-neuronal GABA transporters as targets for anti-epileptic drugs. Pharmacol. Ther., 2010, 125(3), 394-401.
[] [PMID: 20026354]
Borden, L.A.; Dhar, T.G.; Smith, K.E.; Branchek, T.A.; Gluchowski, C.; Weinshank, R.L. Cloning of the human homologue of the GABA transporter GAT-3 and identification of a novel inhibitor with selectivity for this site. Receptors Channels, 1994, 2(3), 207-213.
[PMID: 7874447]
White, H.S.; Sarup, A.; Bolvig, T.; Kristensen, A.S.; Petersen, G.; Nelson, N.; Pickering, D.S.; Larsson, O.M.; Frølund, B.; Krogsgaard-Larsen, P. Correlation between anticonvulsant activity and inhibitory action on glial gamma-aminobutyric acid uptake of the highly selective mouse gamma-aminobutyric acid transporter 1 inhibitor its N-alkylated analogs. J. Pharmacol. Exp. Ther., 2002, 302(2), 636-644.
[] [PMID: 12130726]
Schousboe, A.; Hertz, L. Dale’s Principle and Commu-nication Between Neurones; Pergamon Press, 1983, pp. 113-141.
Krogsgaard-Larsen, P.; Johnston, G.A.R. Inhibition of GABA uptake in rat brain slices by nipecotic acid, various isoxazoles and related compounds. J. Neurochem., 1975, 25(6), 797-802.
[] [PMID: 1206398]
Sitka, I.; Allmendinger, L.; Fülep, G.; Höfner, G.; Wanner, K.T. Synthesis of N-substituted acyclic β-amino acids and their investigation as GABA uptake inhibitors. Eur. J. Med. Chem., 2013, 65, 487-499.
[] [PMID: 23770450]
Clausen, R.P.; Moltzen, E.K.; Perregaard, J.; Lenz, S.M.; Sanchez, C.; Falch, E.; Frølund, B.; Bolvig, T.; Sarup, A.; Larsson, O.M.; Schousboe, A.; Krogsgaard-Larsen, P. Selective inhibitors of GABA uptake: synthesis and molecular pharmacology of 4-N-methylamino-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol analogues. Bioorg. Med. Chem., 2005, 13(3), 895-908.
[] [PMID: 15653355]
Andersen, K.E.; Sørensen, J.L.; Lau, J.; Lundt, B.F.; Petersen, H.; Huusfeldt, P.O.; Suzdak, P.D.; Swedberg, M.D. Synthesis of novel gamma-aminobutyric acid (GABA) uptake inhibitors. 5.(1) Preparation and structure-activity studies of tricyclic analogues of known GABA uptake inhibitors. J. Med. Chem., 2001, 44(13), 2152-2163.
[] [PMID: 11405652]
Sindelar, M.; Lutz, T.A.; Petrera, M.; Wanner, K.T. Focused pseudostatic hydrazone libraries screened by mass spectrometry binding assay: optimizing affinities toward γ-aminobutyric acid transporter 1. J. Med. Chem., 2013, 56(3), 1323-1340.
[] [PMID: 23336362]
Zepperitz, C.; Höfner, G.; Wanner, K.T. MS-binding assays: kinetic, saturation, and competitive experiments based on quantitation of bound marker as exemplified by the GABA transporter mGAT1. ChemMedChem, 2006, 1(2), 208-217.
[] [PMID: 16892353]
Sindelar, M.; Wanner, K.T. Library screening by means of mass spectrometry (MS) binding assays-exemplarily demonstrated for a pseudostatic library addressing γ-aminobutyric acid (GABA) transporter 1 (GAT1). ChemMedChem, 2012, 7(9), 1678-1690.
[] [PMID: 22689508]
Polley, M.; Höfner, G.; Wanner, K.T. Development and validation of an LC-ESI-MS/MS quantification method for a potential γ-aminobutyric acid transporter 3 (GAT3) marker and its application in preliminary MS binding assays. Biomed. Chromatogr., 2013, 27(5), 641-654.
[] [PMID: 23225341]
Schmitt, S.; Höfner, G.; Wanner, K.T. Application of MS transport assays to the four human γ-aminobutyric acid transporters. ChemMedChem, 2015, 10(9), 1498-1510.
[] [PMID: 26220444]
Höfner, G.; Wanner, K.T. Competitive binding assays made easy with a native marker and mass spectrometric quantification. Angew. Chem. Int. Ed. Engl., 2003, 42(42), 5235-5237.
[] [PMID: 14601181]
Li, J.; Nowak, P.; Otto, S. Dynamic combinatorial libraries: from exploring molecular recognition to systems chemistry. J. Am. Chem. Soc., 2013, 135(25), 9222-9239.
[] [PMID: 23731408]
Kern, F.; Wanner, K.T. Screening oxime libraries by means of mass spectrometry (MS) binding assays: Identification of new highly potent inhibitors to optimized inhibitors γ-aminobutyric acid transporter 1. Bioorg. Med. Chem., 2019, 27(7), 1232-1245.
[] [PMID: 30777661]
Lutz, T.; Wein, T.; Höfner, G.; Wanner, K.T. Development of highly potent GAT1 inhibitors: synthesis of nipecotic acid derivatives with N-arylalkynyl substituents. ChemMedChem, 2017, 12(5), 362-371.
[] [PMID: 28125164]
Tóth, K.; Höfner, G.; Wanner, K.T. Synthesis and biological evaluation of novel N-substituted nipecotic acid derivatives with an alkyne spacer as GABA uptake inhibitors. Bioorg. Med. Chem., 2018, 26(12), 3668-3687.
[] [PMID: 29886082]
Tóth, K.; Höfner, G.; Wanner, K.T. Synthesis and biological evaluation of novel N-substituted nipecotic acid derivatives with a cis-alkene spacer as GABA uptake inhibitors. Bioorg. Med. Chem., 2019, 27(5), 822-831.
[] [PMID: 30718063]
Quandt, G.; Höfner, G.; Wanner, K.T. Synthesis and evaluation of N-substituted nipecotic acid derivatives with an unsymmetrical bis-aromatic residue attached to a vinyl ether spacer as potential GABA uptake inhibitors. Bioorg. Med. Chem., 2013, 21(11), 3363-3378.
[] [PMID: 23598250]
Hellenbrand, T.; Höfner, G.; Wein, T.; Wanner, K.T. Synthesis of 4-substituted nipecotic acid derivatives and their evaluation as potential GABA uptake inhibitors. Bioorg. Med. Chem., 2016, 24(9), 2072-2096.
[] [PMID: 27039250]
Steffan, T.; Renukappa-Gutke, T.; Höfner, G.; Wanner, K.T. Design, synthesis and SAR studies of GABA uptake inhibitors derived from 2-substituted pyrrolidine-2-yl-acetic acids. Bioorg. Med. Chem., 2015, 23(6), 1284-1306.
[] [PMID: 25698617]
Huber, S.K.; Höfner, G.; Wanner, K.T. Identification of pyrrolidine-3-acetic acid derived oximes as potent inhibitors of γ-aminobutyric acid transporter 1 through library screening with MS binding assays. ChemMedChem, 2018, 13(23), 2488-2503.
[] [PMID: 30485691]
Huber, S.K.; Höfner, G.; Wanner, K.T. Application of the concept of oxime library screening by mass spectrometry (MS) binding assays to pyrrolidine-3-carboxylic acid derivatives as potential inhibitors of γ-aminobutyric acid transporter 1 (GAT1). Bioorg. Med. Chem., 2019, 27(13), 2753-2763.
[] [PMID: 31097402]
Quandt, G.; Höfner, G.; Pabel, J.; Dine, J.; Eder, M.; Wanner, K.T. First photoswitchable neurotransmitter transporter inhibitor: light-induced control of γ-aminobutyric acid transporter 1 (GAT1) activity in mouse brain. J. Med. Chem., 2014, 57(15), 6809-6821.
[] [PMID: 25025595]
Lutz, T.; Wein, T.; Höfner, G.; Pabel, J.; Eder, M.; Dine, J.; Wanner, K.T. Development of new photoswitchable azobenzene based γ-aminobutyric acid (GABA) uptake inhibitors with distinctly enhanced potency upon photoactivation. J. Med. Chem., 2018, 61(14), 6211-6235.
[] [PMID: 29924931]
Schaarschmidt, M.; Höfner, G.; Wanner, K.T. Synthesis and biological evaluation of nipecotic acid and guvacine derived 1,3-disubstituted allenes as inhibitors of murine GABA transporter mGAT1. ChemMedChem, 2019, 14(12), 1135-1151.
[] [PMID: 30957949]
Hauke, T.J.; Wein, T.; Höfner, G.; Wanner, K.T. Novel allosteric ligands of γ-aminobutyric acid transporter 1 (GAT1) by MS based screening of pseudostatic hydrazone libraries. J. Med. Chem., 2018, 61(22), 10310-10332.
[] [PMID: 30376325]
Hauke, T.J.; Höfner, G.; Wanner, K.T. MS-based screening of 5-substituted nipecotic acid derived hydrazone libraries as ligands of the GABA transporter 1. ChemMedChem, 2019, 14(5), 583-593.
[] [PMID: 30663849]
Suemasa, A.; Watanabe, M.; Kobayashi, T.; Suzuki, H.; Fukuda, H.; Minami, M.; Shuto, S. Design and synthesis of cyclopropane-based conformationally restricted GABA analogues as selective inhibitors for betaine/GABA transporter 1. Bioorg. Med. Chem. Lett., 2018, 28(20), 3395-3399.
[] [PMID: 30177378]
Al-Khawaja, A.; Petersen, J.G.; Damgaard, M.; Jensen, M.H.; Vogensen, S.B.; Lie, M.E.K.; Kragholm, B.; Bräuner-Osborne, H.; Clausen, R.P.; Frølund, B.; Wellendorph, P. Pharmacological identification of a guanidine-containing β-alanine analogue with low micromolar potency and selectivity for the betaine/GABA transporter 1 (BGT1). Neurochem. Res., 2014, 39(10), 1988-1996.
[] [PMID: 24852577]
White, H.S.; Watson, W.P.; Hansen, S.L.; Slough, S.; Perregaard, J.; Sarup, A.; Bolvig, T.; Petersen, G.; Larsson, O.M.; Clausen, R.P.; Frølund, B.; Falch, E.; Krogsgaard-Larsen, P.; Schousboe, A. First demonstration of a functional role for central nervous system betaine/gamma-aminobutyric acid transporter (mGAT2) based on syner-gistic anticonvulsant action among inhibitors of mGAT1 and mGAT2. J. Pharmacol. Exp. Ther., 2005, 312(2), 866-874.
[] [PMID: 15550575]
Dalby, N.O. GABA-level increasing and anticonvulsant effects of three different GABA uptake inhibitors. Neuropharmacology, 2000, 39(12), 2399-2407.
[] [PMID: 10974324]
Thomsen, C.; Sørensen, P.O.; Egebjerg, J. 1-(3-(9H-carbazol-9-yl)-1-propyl)-4-(2-methoxyphenyl)-4-piperidinol, a novel subtype selective inhibitor of the mouse type II GABA-transporter. Br. J. Pharmacol., 1997, 120(6), 983-985.
[] [PMID: 9134205]
Kragler, A.; Höfner, G.; Wanner, K.T. Novel parent struc-tures for inhibitors of the murine GABA transporters mGAT3 and mGAT4. Eur. J. Pharmacol., 2005, 519(1-2), 43-47.
[] [PMID: 16111674]
Kragholm, B.; Kvist, T.; Madsen, K.K.; Jørgensen, L.; Vogensen, S.B.; Schousboe, A.; Clausen, R.P.; Jensen, A.A.; Bräuner-Osborne, H. Discovery of a subtype selective inhibitor of the human betaine/GABA transporter 1 (BGT-1) with a non-competitive pharmacological profile. Biochem. Pharmacol., 2013, 86(4), 521-528.
[] [PMID: 23792119]
Zhao, X.; Hoesl, C.E.; Hoefner, G.C.; Wanner, K.T. Synthesis and biological evaluation of new GABA-uptake inhibitors derived from proline and from pyrrolidine-2-acetic acid. Eur. J. Med. Chem., 2005, 40(3), 231-247.
[] [PMID: 15725493]
Zhao, X.; Pabel, J.; Höfner, G.C.; Wanner, K.T. Synthesis and biological evaluation of 4-hydroxy-4-(4-methoxy-phenyl)-substituted proline and pyrrolidin-2-ylacetic acid derivatives as GABA uptake inhibitors. Bioorg. Med. Chem., 2013, 21(2), 470-484.
[] [PMID: 23245753]
Kerscher-Hack, S.; Renukappa-Gutke, T.; Höfner, G.; Wanner, K.T. Synthesis and biological evaluation of a series of N-alkylated imidazole alkanoic acids as mGAT3 selective GABA uptake inhibitors. Eur. J. Med. Chem., 2016, 124, 852-880.
[] [PMID: 27654218]
Hauke, T.J.; Höfner, G.; Wanner, K.T. Generation and screening of pseudostatic hydrazone libraries derived from 5-substituted nipecotic acid derivatives at the GABA transporter mGAT4. Bioorg. Med. Chem., 2019, 27(1), 144-152.
[] [PMID: 30503411]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy