Anticonvulsant Profiles of the Potent and Orally Active GABA Uptake Inhibitors SK&amp;F 89976‐A and SK&amp;F 100330‐A and Four Prototype Antiepileptic Drugs in Mice and Rats

Ea, Swinyard; Hs, White; Hh, Wolf; We, Bondinell

doi:10.1111/j.1528-1157.1991.tb04694.x

Cited by 24 publications

(11 citation statements)

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“…In support of this principle, a number of GAT1-selective inhibitors have been developed and demonstrated to possess anticonvulsant activity in animal seizure models (Swinyard et al, 1991;Pavia et al, 1992;Suzdak and Jansen, 1995;White et al, 2002;Dalby, 2003). For example, the first peripherally active GABA uptake inhibitor was SKF 89976A [(R)-N-(4,4-diphenyl-3-butenyl) nipecotic acid], an N-substituted diphenyl butenyl analog of nipecotic acid (Swinyard et al, 1991).…”

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confidence: 99%

“…For example, the first peripherally active GABA uptake inhibitor was SKF 89976A [(R)-N-(4,4-diphenyl-3-butenyl) nipecotic acid], an N-substituted diphenyl butenyl analog of nipecotic acid (Swinyard et al, 1991). The corresponding analogs of guvacine, SKF 100330A [N-(4,4-diphenyl-3-butenyl)guvacine] and methoxy]ethyl guvacine], supported the principle that modulation of GABA transport would result in an anticonvulsant action (Swinyard et al, 1991;Pavia et al, 1992). Unfortunately, subsequent clinical trials with CI-966 revealed the potential for serious psychotic adverse effects in certain patients (Radulovic et al, 1993).…”

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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

White

Watson

Hansen

et al. 2004

J Pharmacol Exp Ther

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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- 5,6,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, 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 M, 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.Reduction of GABA-mediated inhibitory neurotransmission is associated with seizure activity and drugs that elevate synaptic GABA levels either by inhibition of GABA degradation or inhibition of high-affinity transport have been demonstrated to possess anticonvulsant activity (see Dalby, 2003;Sarup et al., 2003). For example, the GABA-transaminase inhibitor vigabatrin and the GABA-transport inhibitor tiagabine [(R)-N-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]nipecotic acid] are clinically effective antiepileptic drugs (for review and references, see Ben-Menachem, 2002;Kalviainen, 2002).Since the advent of cloning of several GABA transporters from different species including mouse, rat, and human, in-

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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

White

Watson

Hansen

et al. 2004

J Pharmacol Exp Ther

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“…The bath solution contained (mM): 120 NaCl, 4.7 KCl, 1-2 KH2PO4, 1-2 MgSO4, 2-2 CaCl2, 10 Hepes, 10 dextrose; pH 7-4 and osmolarity, 300 mosmol F-'. Wolf & Bondinell, 1991). GABA-free solution was exchanged for GABAcontaining solutions by a peristaltic pump (flow rate, 1 ml min-).…”

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Sodium‐dependent GABA‐induced currents in GAT1‐transfected HeLa cells.

Risso

DeFelice

Blakely

1996

The Journal of Physiology

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1. HeLa cells were infected with recombinant vaccinia virus containing the T7 RNA polymerase gene and transfected with the cDNA for a rat GABA transporter, GAT1, cloned downstream of a T7 RNA polymerase promoter. Six to sixteen hours after transfection, whole-cell recording with a voltage ramp in the range -90 to 50 mV revealed GABAinduced currents (approximately -100 pA at -60 mV in 100 uM GABA, 16 h after transfection at room temperature). No GABA-induced currents were observed in parental HeLa cells or in mock-transfected cells. 2. GABA-induced currents were suppressed by extracellular perfusion with GABA-free solutions or addition of GATI inhibitors SKF89976-A or SKF100330-A. At fixed voltage the GABA dependence of the inward current fitted the Michaelis-Menten equation with aHill coefficient, n, near unity and an equilibrium constant, Km, near 3 /tM. The Na+ dependence of the inward currents fitted the Michaelis-Menten equation with n t 2 and Km ; 10 mM. The constants n and Km for GABA and Na+ were independent of voltage in the range -90 to -30 mV. 3. GABA-induced currents reverse direction in the range 5-10 mV. The implication of this result is that GAT1 can mediate electrogenic (electrophoretic) influx or efflux of GABA depending on the membrane voltage. The presence of an outward current in our experiments is consistent with radioactive-labelled flux data from resealed vesicle studies. However, it is inconsistent with frog oocyte expression experiments using the same clone. In oocytes, GAT1 generates no outward current in a similar voltage range. Smaller intracellular volume or higher turnover rates in the mammalian expression system may explain the outward currents. 4. External GABA induces inward current, and internal GABA induces outward current.However, in cells initially devoid of internal GABA, external GABA can also facilitate an outward current. This GATi -mediated outward current occurs only after applying negative potentials to the cell. These data are consistent with the concept that negative potentials drive GABA and Nae into the cell, which then leads to electrogenic efflux through GATI at positive voltages. 5. Assuming coupled transport, we estimate the number of transporters, N, times the turnover rate, r, to be Nr t 109 s-' under nominal conditions ( V = -60 mV, 30 /M GABA, 130 mm Nae and room temperature). This indicates either very high levels of expression (0104 um-2), assuming published turnover rates (-1 0 s-1), or turnover rates that are significantly greater than previously reported. As an alternative, a channel may exist in the GAT1 protein that is gated by GABA and Nae and blocked by GAT1 antagonists. The channel mode of conduction would exist in addition to the coupled, fixed-stoichiometry transporter mode of conduction.

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“…Efforts to develop specific inhibitors of the GABA transporters have led to the identification of multiple compounds that have been shown to possess anticonvulsant activity in preclinical animal seizure models (Yunger et al, 1984;Krogsgaard-Larsen et al, 1987;Swinyard et al, 1991;White et al, 1993;Borden et al, 1994;Suzdak, 1995;Bolvig et al, 1999;Schousboe et al, 2004a;White et al, 2005). EF1502 (N-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-4-(methylamino-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol), the Nsubstituted analogue of exo- 5,6,isoxazol-3-ol) noncompetitively inhibits both GAT1 and GAT2 (White et al, 2005;Clausen et al, 2006).…”

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confidence: 99%

Inhibition of the betaine-GABA transporter (mGAT2/BGT-1) modulates spontaneous electrographic bursting in the medial entorhinal cortex (mEC)

Smith¹,

Saunders²,

Clausen³

et al. 2008

Epilepsy Research

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Disruptions in GABAergic neurotransmission have been implicated in numerous CNS disorders, including epilepsy and neuropathic pain. Selective inhibition of neuronal and glial GABA transporter subtypes may offer unique therapeutic options for regaining balance between inhibitory and excitatory systems. The ability of two GABA transport inhibitors to modulate inhibitory tone via inhibition of mGAT1 (tiagabine) or mGAT2/BGT-1 (N-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-4-(methylamino-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol), also known as EF1502) was evaluated using an in vitro model of spontaneous interictal-like bursting (SB). SBs were recorded extracellularly in combined mEC-HC horizontal brain slices (400 μm; 31 ± 1°C) obtained from KA-treated rats. Slice recordings demonstrated that EF1502 exhibited a concentration-dependent reduction in SB frequency. EF1502 significantly reduced SB rate to 32% of control at the 30 μM concentration, while reducing the area and duration of SB activity to 60% and 46% of control, respectively, at the 10 μM concentration. In contrast, the GAT1 selective inhibitor tiagabine (3, 10, and 30 μM) was unable to significantly reduce the frequency of SB activity in the mEC, despite significantly reducing both the duration (51% of control) and area (58% of control) of the SB at concentrations as low as 3 μM. The ability of EF1502, but not tiagabine, to inhibit SBs in the mEC suggests that this in vitro model of pharmacoresistant SB activity is useful to differentiate between novel anticonvulsants with similar mechanisms of action and suggests a therapeutic potential for non-GAT1 transport inhibitors.

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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

Cited by 24 publications

References 24 publications

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

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

Sodium‐dependent GABA‐induced currents in GAT1‐transfected HeLa cells.

Inhibition of the betaine-GABA transporter (mGAT2/BGT-1) modulates spontaneous electrographic bursting in the medial entorhinal cortex (mEC)

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