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NEUROPHARMACOLOGY

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

Anticonvulsant Drug Development Program, Department of Pharmacology and Toxicology (H.S.W.), University of Utah, Salt Lake City, Utah; Departments of Neuropharmacology (W.P.W., S.L.H., S.S.) and Medicinal Chemistry (J.P.) H. Lundbeck A/S, Valby, Denmark; and Departments of Pharmacology (A.Sa., T.B., G.P., O.M.L., A.Sc.) and Medicinal Chemistry (R.P.C., B.F., E.F., P.K.-L.), The Danish University of Pharmaceutical Sciences, Copenhagen, Denmark

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-spectrum anticonvulsant profile in animal models of generalized and partial epilepsy. When EF1502 was tested in combination with the clinically effective GAT1-selective inhibitor tiagabine [(R)-N-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]nipecotic acid] or LU-32-176B [N-[4,4-bis(4-fluorophenyl)-butyl]-3-hydroxy-4-amino-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol], another GAT1-selective N-substituted analog of exo-THPO, a synergistic rather than additive anticonvulsant interaction was observed in the Frings audiogenic seizure-susceptible mouse and the pentylenetetrazol seizure threshold test. In contrast, combination of the two mGAT1-selective inhibitors, tiagabine and LU-32-176B, resulted in only an additive anticonvulsant effect. Importantly, the combination of EF1502 and tiagabine did not result in a greater than additive effect in the rotarod behavioral impairment test. In subsequent in vitro studies conducted in HEK-293 cells expressing the cloned mouse GAT transporters mGAT1 and mGAT2, EF1502 was found to noncompetitively inhibit both mGAT1 and the betaine/GABA transporter mGAT2 (K_i of 4 and 5 µM, respectively). Furthermore, in a GABA release study conducted in neocortical neurons, EF1502 did not act as a substrate for the GABA carrier. Collectively, these findings support a functional role for mGAT2 in the control of neuronal excitability and suggest a possible utility for mGAT2-selective inhibitors in the treatment of epilepsy.

Address correspondence to: Dr. H. Steve White, University of Utah, Anticonvulsant Drug Development Program, Department of Pharmacology and Toxicology, 20 S. 2030 E., Room 408, Salt Lake City, UT 84112. E-mail: swhite{at}hsc.utah.edu

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				B. Christiansen, A.-K. Meinild, A. A. Jensen, and H. Brauner-Osborne Cloning and Characterization of a Functional Human {gamma}-Aminobutyric Acid (GABA) Transporter, Human GAT-2 J. Biol. Chem., July 6, 2007; 282(27): 19331 - 19341. [Abstract] [Full Text] [PDF]