Anticonvulsant properties of two GABA uptake inhibitors NNC 05-2045 and NNC 05-2090, not acting preferentially on GAT-1

Dalby, Nils Ole; Thomsen, C.; Fink-Jensen, Anders; Lundbeck, Jane M.; Søkilde, Birgitte; Man, Chiu Ming; Sørensen, Per O.; Meldrum, Brian S.

doi:10.1016/s0920-1211(97)00033-8

Cited by 49 publications

(17 citation statements)

References 28 publications

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“…To this end, Dalby et al (1997) have demonstrated that such inhibitors may be interesting as antiepileptic drugs. For example, it was reported that inhibitors of GAT3 and GAT4 afforded protection against maximal electroshock, audiogenic, and kindled seizures (Dalby et al, 1997) Unfortunately, these inhibitors, which structurally are not GABA mimetics , were shown to have affinity for ␣-1 adrenergic and D-2 dopamine receptors (Dalby et al, 1997). As such, it is difficult to make any definitive conclusion regarding the mechanism underlying their anticonvulsant action.…”

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confidence: 99%

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. 2005

The Journal of Pharmacology and Experimental Therapeutics

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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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confidence: 99%

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. 2005

The Journal of Pharmacology and Experimental Therapeutics

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“…We concluded that the inhibitory effects of NNC 05-2090 on BGT-1 were more selective than those of the other GATs. NNC05-2090 also exhibited a 1 -and D 2 -receptor affinities of 266 and 1632 nM, respectively (43). Previous studies reported the anticonvulsant effects of NNC05-2090 in rodent seizure models (43).…”

Section: Discussionmentioning

confidence: 97%

“…NNC05-2090 also exhibited a 1 -and D 2 -receptor affinities of 266 and 1632 nM, respectively (43). Previous studies reported the anticonvulsant effects of NNC05-2090 in rodent seizure models (43). They also reported that the inhibition of GAT through non-GAT-1 transporters induced anticonvulsant effects that differed from those of selective GAT-1 inhibitors (e.g., tiagabine).…”

Section: Discussionmentioning

confidence: 99%

Antiallodynic Action of 1-(3-(9H-Carbazol-9-yl)-1-propyl)-4-(2-methyoxyphenyl)-4-piperidinol (NNC05-2090), a Betaine/GABA Transporter Inhibitor

et al. 2014

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Abstract. The GABAergic system in the spinal cord has been shown to participate in neuropathic pain in various animal models. GABA transporters (GATs) play a role in controlling the synaptic clearance of GABA; however, their role in neuropathic pain remains unclear. In the present study, we compared the betaine/GABA transporter (BGT-1) with other GAT subtypes to determine its participation in neuropathic pain using a mouse model of sciatic nerve ligation. 1-(3-(9H-Carbazol-9-yl)-1-propyl)-4-(2-methyoxyphenyl)-4-piperidinol (NNC05-2090), an inhibitor that displays moderate selectivity for BGT-1, had an antiallodynic action on model mice treated through both intrathecally and intravenous administration routes. On the other hand, SKF89976A, a selective GAT-1 inhibitor, had a weak antiallodynic action, and (S)-SNAP5114, an inhibitor that displays selectivity for GAT-3, had no antiallodynic action. Systemic analysis of these compounds on GABA uptake in CHO cells stably expressing BGT-1 revealed that NNC05-2090 not only inhibited BGT-1, but also serotonin, noradrenaline, and dopamine transporters, using a substrate uptake assay in CHO cells stably expressing each transporter, with IC 50 : 5.29, 7.91, and 4.08 mM, respectively. These values were similar to the IC 50 value at BGT-1 (10.6 mM). These results suggest that the antiallodynic action of NNC05-2090 is due to the inhibition of both BGT-1 and monoamine transporters.

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“…9,10 Successful development of potent and highly selective inhibitors of GABA transporters other than GAT-1, however, has not been achieved. EF1502, 11−13 NNC05-2090, 14,15 and tiagabine analogue A…”

Section: * S Supporting Informationmentioning

confidence: 99%

Conformationally Restricted GABA with Bicyclo[3.1.0]hexane Backbone as the First Highly Selective BGT-1 Inhibitor

Kobayashi

Suemasa

Igawa

et al. 2014

ACS Med. Chem. Lett.

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On the basis of the three-dimensional diversity-oriented conformational restriction strategy using key chiral cyclopropane units, we previously identified 3 ((2S,3R)-4-amino-3,4-methanobutyric acid) with a chiral trans-cyclopropane structure as a γ-aminobutyric acid (GABA) transporter inhibitor selective for GABA transporter (GAT) subtypes GAT-3 and BGT-1 (betaine/GABA transporter-1). Further conformational restriction of 3 with the rigid bicyclo[3.1.0]hexane backbone led to the successful development of the first highly potent and selective BGT-1 inhibitor 4 (IC 50 = 0.59 μM). The bioactive conformation of 3 for BGT-1 was also identified.

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Anticonvulsant properties of two GABA uptake inhibitors NNC 05-2045 and NNC 05-2090, not acting preferentially on GAT-1

Cited by 49 publications

References 28 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

Antiallodynic Action of 1-(3-(9H-Carbazol-9-yl)-1-propyl)-4-(2-methyoxyphenyl)-4-piperidinol (NNC05-2090), a Betaine/GABA Transporter Inhibitor

Conformationally Restricted GABA with Bicyclo[3.1.0]hexane Backbone as the First Highly Selective BGT-1 Inhibitor

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