Selective inhibitors of GABA uptake: synthesis and molecular pharmacology of 4-N-methylamino-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol analogues

Clausen, Rasmus P.; Moltzen, Ejner K.; Perregaard, Jens; Lenz, Sibylle M.; Sanchéz, Connie; Falch, Erik; Frølund, Bente; Bolvig, Tina; Sarup, Alan; Larsson, Orla M.; Schousboe, Arne; Krogsgaard‐Larsen, Povl

doi:10.1016/j.bmc.2004.10.029

Cited by 81 publications

(69 citation statements)

References 45 publications

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“…In contrast to the parent compounds THPO and N-methyl-THPO, of which the latter has been shown to be a glialselective GABA uptake inhibitor White et al, 2002), the lipophilic analogs of these compounds described here did not exhibit cell-type selectivity (Clausen et al, 2005). However, EF1502, the lipophilic analog of N-methyl-exo-THPO, was found to display significant affinity for mGAT2 as well as mGAT1.…”

Section: Discussioncontrasting

confidence: 72%

“…However, EF1502, the lipophilic analog of N-methyl-exo-THPO, was found to display significant affinity for mGAT2 as well as mGAT1. This was not the case for EF1500, its non-N-methylated counterpart (Clausen et al, 2005). That this N-methyl group (see Fig.…”

Section: Discussionmentioning

confidence: 90%

“…The inhibition profiles of tiagabine and the exo-THPO analogs (see Fig. 1) on GABA uptake in neurons and astrocytes as well as HEK cells transfected with the cloned mouse GABA transporters mGAT1 to 4 obtained in a recently conducted study (Clausen et al, 2005) are summarized in Table 1. It can be seen that EF1502 (the dithienyl-butenyl analog of N-methyl-exo-THPO), in contrast to tiagabine (the dithienyl-butenyl analog of nipecotic acid), exhibited pronounced inhibitory activity toward mGAT2, whereas mGAT3 and mGAT4 were only weakly inhibited.…”

Section: Resultsmentioning

confidence: 99%

“…[ 3 H]GABA (79.0 Ci/mmol) was from DuPont-NEN (Frankfurt, Germany). Exo-THPO and its N-substituted analogs were synthesized as described previously (Clausen et al, 2005). Tiagabine was generously provided by Sanofi Synthelabo (Brøndby, Denmark).…”

Section: Methodsmentioning

confidence: 99%

“…1) that have been shown to inhibit to varying degrees GABA transporters other than GAT1 (Clausen et al, 2005). Of particular interest is the analog 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 was found to equipotently inhibit both mGAT1 and mGAT2 and was completely devoid of activity at a multitude of neurotransmitter systems including adrenergic, GABAergic, and dopaminergic receptors (radioligand binding study of 74 different receptors and ion channels; data not shown).…”

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confidence: 99%

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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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Section: Discussioncontrasting

confidence: 72%

Section: Discussionmentioning

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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