Disease relevance of R 72063

• These data suggest that the broad-spectrum antiepileptic loreclezole can be a valuable new drug in the treatment of absence epilepsy [1].
• In animal models of epilepsy the anticonvulsant profile of loreclezole resembles that of barbiturates and benzodiazepines [2].
• Major metrazol seizures, i.e., generalized tonic-clonic seizures, were suppressed by loreclezole in a dose-dependent manner in all age-groups, except in the 7 day old group where outlined changes did not reach statistical significance [3].

Psychiatry related information on R 72063

• The beta2N265S mice did not exhibit loreclezole-mediated sedation as shown by normal locomotor activity and beam walking performance [4].
• This study examined the interaction characteristics between loreclezole (LCZ) and various conventional antiepileptic drugs (phenytoin - PHT, carbamazepine - CBZ, valproate - VPA and phenobarbital - PB) in the mouse maximal electroshock (MES)-induced seizure model using isobolographic analysis [5].

High impact information on R 72063

• Using different combinations of human GABAA receptor subunits expressed in Xenopus oocytes and transfected 293 cells, loreclezole was highly selective for receptors containing the beta 2 or beta 3 subunit over those containing the beta 1 subunit [6].
• The action of loreclezole depends on the type of beta subunit present in the receptor complex; receptors containing beta 2 or beta 3 subunits have > 300-fold higher affinity for loreclezole than receptors containing a beta 1 subunit [7].
• 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 [7].
• The rank order of potentiation for pregnanolone was alpha5 > alpha2 > alpha3 = alpha4 > alpha1, for loreclezole alpha1 = alpha2 = alpha3 > alpha5 > alpha4, and for pentobarbital alpha4 = alpha5 = alpha2 > alpha1 = alpha3 [8].
• This acceleration was prevented by 7-chlorokynurenic acid, a glycine antagonist at the NMDA receptor complex, and by the GABA agonist loreclezole [9].

Biological context of R 72063

• beta-Carboline gamma-aminobutyric acidA receptor inverse agonists modulate gamma-aminobutyric acid via the loreclezole binding site as well as the benzodiazepine site [10].
• Other binding data suggested that although the evidence of others indicates that loreclezole interacts with a specific allosteric site on the beta-subunit, it nevertheless also alters the binding characteristics of other modulatory sites [11].
• All three compounds fully displaced [35S]TBPS binding (IC50 values: loreclezole, 4.34 +/- 0.68 microM; pentobarbitone, 37.39 +/- 3.24 microM; chlormethiazole, 82.10 +/- 8.52 microM) [11].

Anatomical context of R 72063

• We used patch-clamp recording from outside-out and inside-out patches from L929 fibroblasts transiently transfected with rat GABAR subunits to examine the properties of inhibition of alpha1beta1gamma2L single channel currents by loreclezole [12].
• 4. In the [3H]-FNZ binding studies on well-washed membranes, loreclezole enhanced binding to a maximum of 47.3 +/- 2.83% of control (mean +/- s.e.mean, n = 3) at 300 microM [13].
• The recurrent discharges in the entorhinal cortex were reliably blocked by 80 microM loreclezole applied for 80-100 min [14].
• The recurrent short discharges in the hippocampus were reliably blocked by 40 muM loreclezole 60-90 min after bath application with incomplete recovery after washout of several hours [14].
• The rapid onset of activity indicates that loreclezole readily passes the blood-brain barrier [15].

Associations of R 72063 with other chemical compounds

• We were interested to know how receptors containing both beta1 and beta2 subunits, in different positions respond to loreclezole and etomidate [16].
• Thymol (1-100 microm) potentiation of responses to EC20 GABA for alpha1beta1gamma2s, alpha6beta3gamma2s and alpha1beta3gamma2s human GABAA receptors was almost identical, arguing against actions at benzodiazepine or loreclezole sites [17].
• These data suggest that loreclezole shares, with propofol, an agonistic action at GABAA receptors containing the beta 2-subunit and that the different efficacies of the two compounds in this regard, may underlie the difference in their pharmacological profiles [18].
• A number of drugs presently under development, such as NMDA receptor antagonists, loreclezole, losigamone, methysticine, and dextromethorphan, are promising in acute animal models of otherwise drug-resistant convulsant activity [19].
• Diflunisal was the most efficacious compound, eliciting greater potentiation than loreclezole (90 +/- 14% and 109 +/- 14% at beta3 and beta2, respectively, compared with 62 +/- 6% and 56 +/- 3%), whereas niflumic acid exhibited the lowest efficacy [20].

Gene context of R 72063

• By mutating single amino acids of the beta 1 subunit to the beta 2/beta 3 equivalent, only the beta 1 mutation of Ser-290-->Asn conferred potentiation by loreclezole [7].
• Loreclezole enhances apparent desensitization of recombinant GABAA receptor currents [21].
• It has been known that neurosteroids and barbiturates are uniformly active in both the two subunit receptors, substituted pyrazinones are only active in the alpha 1 beta 2 subtype and loreclezole is active in the subtypes containing beta 2 [22].
• Thirteen drug-resistant epilepsy patients received loreclezole as add-on therapy [23].
• The effects of loreclezole and La3+ on native cerebellar GABA(A) receptors were compared between GABA(A) receptor alpha6 subunit-deficient (alpha6-/-) and wildtype mouse lines, produced through homologous recombination, using t-[35S]butylbicyclophosphorothionate ([35S]TBPS) autoradiography in brain sections [24].

Analytical, diagnostic and therapeutic context of R 72063

• In addition, the effects of 0, 5, 10 and 20 mg/kg loreclezole on the spectral content of the background EEG and on spontaneous behaviour of rats were investigated [1].

References