Loreclezole (R 72 063): An anticonvulsant chemically unrelated to prototype antiepileptic drugs

Wauquier, A.; Fransen, J.; Melis, W.; Ashton, David; Gillardin, Jean-Marie; Lewi, Paul; Clemen, Gust van; Vaught, Jeffrey; Janßen, Paul

doi:10.1002/ddr.430190404

Cited by 30 publications

(7 citation statements)

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“…(Arylalkyl)azoles (AAAs) emerged as a class of antiepileptic compounds with the development of nafimidone, denzimol, and loreclezole (LRZ) (Fig. ) . Nafimidone and denzimol have similar activity profiles to phenytoin and carbamazepine, which inhibit voltage‐gated sodium channels (VGSCs) and enhance γ‐aminobutyric acid (GABA)‐mediated response .…”

Section: Introductionmentioning

confidence: 99%

New Anti‐Seizure (Arylalkyl)azole Derivatives: Synthesis, In Vivo and In Silico Studies

Sarı

Dalkara

Kaynak

et al. 2017

Archiv der Pharmazie

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(Arylalkyl)azoles are a class of antiepileptic compounds including nafimidone, denzimol, and loreclezole (LRZ). Nafimidone and denzimol are thought to inhibit voltage-gated sodium channels (VGSCs) and enhance γ-aminobutyric acid (GABA)-mediated response. LRZ, a positive allosteric modulator of A-type GABA receptors (GABA Rs), was reported to be sensitive to Asn265 of the β2/β3 subunit. Here, we report new N-[1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)ethylidene]hydroxylamine esters showing anticonvulsant activity in animal models, including the 6-Hz psychomotor seizure test, a model for therapy-resistant partial seizure. We performed molecular docking studies for our active compounds using GABA R and VGSC homology models. They predicted high affinity to the benzodiazepine binding site of GABA R in line with the experimental results. Also, the binding mode and interactions of LRZ in its putative allosteric binding site of GABA R is elucidated.

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Section: Introductionmentioning

confidence: 99%

New Anti‐Seizure (Arylalkyl)azole Derivatives: Synthesis, In Vivo and In Silico Studies

Sarı

Dalkara

Kaynak

et al. 2017

Archiv der Pharmazie

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“…Mice genetically modified to lack β3 expression exhibit a number of neurological and developmental abnormalities including an epileptic‐like phenotype (Homanics et al ., 1997). Furthermore, the potent yet sedative broad‐spectrum anticonvulsant loreclezole (Waquier et al ., 1990) is primarily a potentiator of β2 and β3 subunit‐containing GABA A receptors (greater than 100‐fold over those containing β1; Wafford et al ., 1994). Loreclezole also modulates ρ‐containing GABA C , (Thomet et al ., 2000), and probably θ‐containing GABA A receptors (based on its similar profile to etomidate; Ranna et al ., 2006).…”

Section: Introductionmentioning

confidence: 99%

The role of GABA_Aβ2 subunit‐containing receptors in mediating the anticonvulsant and sedative effects of loreclezole

Groves

Guscott

Hallett

et al. 2006

Eur J of Neuroscience

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The majority of inhibitory neurotransmission in the brain is mediated by the gamma-aminobutyric acid (GABA) type A (GABA(A)) receptor. The anticonvulsant loreclezole largely acts by potentiating GABA(A) receptors containing beta2 and beta3 subunits. We used a genetically modified mouse containing a loreclezole-insensitive beta2 subunit (beta2N265S) to determine the role of this subunit in mediating the sedative and anticonvulsive effects of loreclezole. Sedation was assessed by measuring spontaneous locomotor activity and beam walking performance, and anticonvulsant efficacy was determined by pentylenetetrazole (PTZ) and amygdala kindling-induced seizures. The beta2N265S mice did not exhibit loreclezole-mediated sedation as shown by normal locomotor activity and beam walking performance. However, loreclezole also failed to provide significant protection against PTZ-induced seizures in the beta2N265S mice. Reduced efficacy against amygdala-kindled seizures, both acutely and over a 13-day chronic dosing study, was also observed in beta2N265S mice. These results suggest that the majority of the sedative effects and a significant proportion of the anticonvulsant efficacy of loreclezole are mediated via beta2-containing GABA(A) receptors.

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“…Loreclezole, {(Z)-1-[2-chloro-2-(2,4-dichlorophenyl) ethenyl]-1,2,4-triazole}, is a broad-spectrum anticonvulsant compound that was suggested to act via the GABAA receptor (14,15). Until recently the precise mode of action of loreclezole was unclear.…”

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The modulatory action of loreclezole at the gamma-aminobutyric acid type A receptor is determined by a single amino acid in the beta 2 and beta 3 subunit.

Wingrove

Wafford

Bain

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

218

129

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Type A yaminobutyric acid (GABAA) receptors of the mammalian nervous system are a family of ligandgated ion channels probably formed from the coassembly of different subunits (a1.6, Pl39 8) in the arrangement apy or ad8. The activation of these receptors by GABA can be modulated by a range ofcompounds acting at distinct allosteric sites. One such compound is the broad-spectrum anticonvulsant loreclezole, which we have recently shown to act via a specific modulatory site on the P subunit of the GABAA receptor. The action of loreclezole depends on the type of 13 subunit present in the receptor complex; receptors containing P2 or 13 subunits have >300-fold higher affinity for loreclezole than receptors containing a PI subunit. We have used this property to identify the amino acid residue in the P subunit that determines the subunit selectivity of loreclezole. Chimeric P1/12 human GABAA receptor subunits were constructed and coexpressed in Xenopus oocytes with human a, and y subunits. The chimera 131/P2Lys237-Gly334 conferred sensitivity to 1 IAM loreclezole. Within this region there are four amino acids that are conserved in P2 and 13 but differ in 1. By mutating single amino acids of the P1 subunit to the P2/13 equivalent, only the P1 mutation of Ser-290 -* Asn conferred potentiation by loreclezole. Similarly, mutation of the homologous residue in the 12 and P3 subunits to the Pi equivalent (Asn --Ser) resulted in loss of sensitivity to loreclezole. The affinity for GABA and the potentiation by flunitrazepam were unchanged in receptors coning the mutated 13 subunits. Thus, a single amino acid, 12 Asn-289 (P1 Asn-290), located at the carboxyl-terminal end of the putative channel-lining domain TM2, confers sensitivity to the modulatory effects of loreclezole.The mammalian type A )-aminobutyric acid (GABAA) receptor gene family is now known to consist of a number of subunit polypeptides (al-a6, (31-P3, 3v-y3. 6, pi-p2) (1, 2).There is an increased body of evidence that suggests that in neurons these subunits coassemble in the arrangement a(yor a(3S (3,4), probably as pentamers (by analogy with the related nicotinic receptor), to give a family of receptor subtypes that have different spatial and temporal patterns ofexpression (5).The activity of GABAA receptors can be allosterically modulated by a number of agents, including ethanol and neurosteroids, and the clinically important barbiturates and benzodiazepines (BZs) (6, 7). The BZ pharmacology of GABAA receptor subtypes has been studied in some detail.Only receptors made up of an a, 3, and 'y subunit exhibit high-affinity BZ binding (8), and the pharmacology is determined by the type of a (9-11) and y (12), but not the (, (13), subunit present, suggesting that this modulatory site is constituted by determinants on both the a and y subunits. The structural determinants that contribute to the other modulatory sites of the GABAA receptor are currently unclear.Loreclezole, {(Z)-1-[2-chloro-2-(2,4-dichlorophenyl) ethenyl]-1,2,4-triazole}, is a broad-spectrum anti...

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Loreclezole (R 72 063): An anticonvulsant chemically unrelated to prototype antiepileptic drugs

Cited by 30 publications

References 10 publications

New Anti‐Seizure (Arylalkyl)azole Derivatives: Synthesis, In Vivo and In Silico Studies

New Anti‐Seizure (Arylalkyl)azole Derivatives: Synthesis, In Vivo and In Silico Studies

The role of GABA_Aβ2 subunit‐containing receptors in mediating the anticonvulsant and sedative effects of loreclezole

The modulatory action of loreclezole at the gamma-aminobutyric acid type A receptor is determined by a single amino acid in the beta 2 and beta 3 subunit.

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Loreclezole (R 72 063): An anticonvulsant chemically unrelated to prototype antiepileptic drugs

Cited by 30 publications

References 10 publications

New Anti‐Seizure (Arylalkyl)azole Derivatives: Synthesis, In Vivo and In Silico Studies

New Anti‐Seizure (Arylalkyl)azole Derivatives: Synthesis, In Vivo and In Silico Studies

The role of GABAAβ2 subunit‐containing receptors in mediating the anticonvulsant and sedative effects of loreclezole

The modulatory action of loreclezole at the gamma-aminobutyric acid type A receptor is determined by a single amino acid in the beta 2 and beta 3 subunit.

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The role of GABA_Aβ2 subunit‐containing receptors in mediating the anticonvulsant and sedative effects of loreclezole