First Demonstration of a Functional Role for Central Nervous System Betaine/γ-Aminobutyric Acid Transporter (mGAT2) Based on Synergistic Anticonvulsant Action among Inhibitors of mGAT1 and mGAT2

@article{White2005FirstDO,
  title={First Demonstration of a Functional Role for Central Nervous System Betaine/$\gamma$-Aminobutyric Acid Transporter (mGAT2) Based on Synergistic Anticonvulsant Action among Inhibitors of mGAT1 and mGAT2},
  author={H. Steve White and William Patrick Watson and Suzanne L. Hansen and Scott Slough and Jens Kristian Perregaard and Alan Sarup and Tina Bolvig and Gitte Petersen and Orla Miller Larsson and Rasmus Pr{\ae}torius Clausen and Bente Fr{\o}lund and Erik Falch and Povl Krogsgaard‐Larsen and Arne Schousboe},
  journal={Journal of Pharmacology and Experimental Therapeutics},
  year={2005},
  volume={312},
  pages={866 - 874}
}
In a recent study, EF1502 [N-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-hydroxy-4-(methylamino)-4,5,6,7-tetrahydrobenzo [d]isoxazol-3-ol], which is an N-substituted analog of the GAT1-selective GABA uptake inhibitor exo-THPO (4-amino-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol), was found to inhibit GABA transport mediated by both GAT1 and GAT2 in human embryonic kidney (HEK) cells expressing the mouse GABA transporters GAT1 to 4 (mGAT1–4). In the present study, EF1502 was found to possess a broad… 

Figures and Tables from this paper

Selective GABA Transporter Inhibitors Tiagabine and EF1502 Exhibit Mechanistic Differences in Their Ability to Modulate the Ataxia and Anticonvulsant Action of the Extrasynaptic GABAA Receptor Agonist Gaboxadol
TLDR
The mechanistic differences between tiagabine and EF1502 are highlighted and support a functional role for BGT1 and extrasynaptic GABAA receptors.
Pharmacological Characterization of a Betaine/GABA Transporter 1 (BGT1) Inhibitor Displaying an Unusual Biphasic Inhibition Profile and Anti-seizure Effects
TLDR
Animal studies revealed anti-seizure effects of SBV2-114 in two mouse models, supporting a function of BGT1 in epilepsy and the molecular mechanism of an emerging biphasic profile of B GT1-mediated GABA transport and the putative involvement of two binding sites for this class of compounds.
Pharmacological Identification of a Guanidine-Containing β-Alanine Analogue with Low Micromolar Potency and Selectivity for the Betaine/GABA Transporter 1 (BGT1)
TLDR
The guanidine-containing compound 9 (2-amino-1,4,5,6-tetrahydropyrimidine-5-carboxylic acid hydrochloride) is the most potent inhibitor reported to date for this subtype and is the first small-molecule substrate identified with such a high selectivity for BGT1 over the three other GAT subtypes.
Pharmacological Characterization of [3H]ATPCA as a Substrate for Studying the Functional Role of the Betaine/GABA Transporter 1 and the Creatine Transporter.
TLDR
[3H]ATPCA is reported as a novel radioactive substrate for both BGT1 and CreaT, and the dual activity of the radioligand makes it most suitable for use in recombinant studies.
Exploring the molecular determinants for subtype-selectivity of 2-amino-1,4,5,6-tetrahydropyrimidine-5-carboxylic acid analogs as betaine/GABA transporter 1 (BGT1) substrate-inhibitors
TLDR
The binding mode of 20 novel analogs is characterized and the molecular determinants driving BGT1-selectivity are proposed to guide the rational design of BGT2-selective pharmacological tool compounds for future drug discovery.
...
...

References

SHOWING 1-10 OF 46 REFERENCES
Correlation between Anticonvulsant Activity and Inhibitory Action on Glial γ-Aminobutyric Acid Uptake of the Highly Selective Mouse γ-Aminobutyric Acid Transporter 1 Inhibitor 3-Hydroxy-4-amino-4,5,6,7-tetrahydro-1,2-benzisoxazole and ItsN-Alkylated Analogs
TLDR
Results obtained with the N-methyl-exo-THPO prodrug demonstrate the feasibility of developing a glial-selective GABA uptake inhibitor with systemic bioavailability and suggest a correlation between anticonvulsant efficacy and selective inhibition of astroglial GABA uptake.
Selective inhibitors of GABA uptake: synthesis and molecular pharmacology of 4-N-methylamino-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol analogues.
Action of bicyclic isoxazole GABA analogues on GABA transporters and its relation to anticonvulsant activity.
Selective inhibitors of glial GABA uptake: synthesis, absolute stereochemistry, and pharmacology of the enantiomers of 3-hydroxy-4-amino-4,5,6,7-tetrahydro-1,2-benzisoxazole (exo-THPO) and analogues.
TLDR
The target compounds were synthesized by regioselective chromic acid oxidation of the respective bicyclic tetrahydrobenzenes 19a,b and 50, and they were used as key intermediates for the syntheses of the target zwitterionic 3-isoxazolols 8-15 and 3- isothiazolols 16 and 17, respectively.
Identification of a pyridinium metabolite in human urine following a single oral dose of 1-[2-[bis[4-(trifluoromethyl)phenyl]methoxy]ethyl]- 1,2,5,6-tetrahydro-3-pyridinecarboxylic acid monohydrochloride, a gamma-aminobutyric acid uptake inhibitor.
TLDR
An unknown urinary component was identified as a pyridinium metabolite of CI-966 based on HPLC-MS and 1H and 19F NMR and Structural confirmation was achieved by chromatographic and spectroscopic comparisons to a reference standard.
A Review of the Preclinical Pharmacology of Tiagabine: A Potent and Selective Anticonvulsant GABA Uptake Inhibitor
TLDR
The overall biochemical and anticonvulsant profile of TGB suggests potential utility in the treatment of chronic seizure disorders such as generalized clonic‐tonic epilepsy, photomyoclonic seizures, myoclonic petit mal epilepsy, and complex partial epilepsy.
Anticonvulsant Profiles of the Potent and Orally Active GABA Uptake Inhibitors SK&F 89976‐A and SK&F 100330‐A and Four Prototype Antiepileptic Drugs in Mice and Rats
TLDR
The data support the concept that SK&F 89976‐A andSK&F 100330‐A may be useful in treatment of partial seizures and suggest that these compounds raise the threshold for seizure initiation rather than inhibit seizure spread.
Kinetic Characterization of Inhibition of γ‐Aminobutyric Acid Uptake into Cultured Neurons and Astrocytes by 4,4‐Diphenyl‐3‐Butenyl Derivatives of Nipecotic Acid and Guvacine
TLDR
The effects of N‐(4,4‐diphenyl‐3‐butenyl) derivatives of nipecotic acid and guvacine on neuronal and astroglial γ‐aminobutyric acid (GABA) uptake were investigated and the competitive nature of SKF‐89976‐A was found to be competitive.
Excitatory amino acid-induced release of 3H-GABA from cultured mouse cerebral cortex interneurons
TLDR
The development of binding sites for the different EAA-receptor subtypes showed a good correlation with the development of neuronal 3H-GABA release evoked by the excitatory amino acids.
...
...