title: A behavioural and neurochemical study in rats of the pharmacology of loreclezole, a novel allosteric modulator of the GABAA receptor.
abstract: Loreclezole is an anticonvulsant and anxiolytic compound which has been reported to potentiate GABA via a novel allosteric site on the beta-subunit of the receptor. We have now studied in rats both the in vivo and in vitro pharmacology of the compound. The dose of loreclezole required to increase by 50% the dose of intravenous pentylenetetrazol eliciting a seizure was comparable to that of barbiturates and chlormethiazole (in mg/kg): diazepam, 1.3; pentobarbitone, 16; chlormethiazole, 22; loreclezole, 25; pentobarbitone, 36. Loreclezole dose-dependently decreased locomotion (dose to decrease locomotion by 50% (in mg/kg): chlormethiazole, 9; pentobarbitone, 16; loreclezole, 25). Loreclezole, chlormethiazole and pentobarbitone all failed to displace [3H]muscimol and [3H]flunitrazepam binding from a rat cortical membrane preparation. 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). Addition of bicuculline (10 microM) produced a major rightward shift in the loreclezole and pentobarbitone displacement curves, increasing IC50 values for [35S]TBPS binding by 25 times (loreclezole), 6 times (pentobarbitone) and 2.7 times (chlormethiazole), suggesting a greater involvement of GABA in the interaction of loreclezole with the chloride channel than in the case of chlormethiazole. Anticonvulsant activity of the compounds did not appear to relate to [35S]TBPS binding activity. 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.
authors.affiliation: Astra Neuroscience Research Unit, London, U.K.
authors.forename: A R
authors.initials: AR
authors.lastname: Green
authors.forename: A
authors.initials: A
authors.lastname: Misra
authors.forename: T K
authors.initials: TK
authors.lastname: Murray
authors.forename: M F
authors.initials: MF
authors.lastname: Snape
authors.forename: A J
authors.initials: AJ
authors.lastname: Cross
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001923:Brain Chemistry / Q000187:drug effects*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D002719:Chlormethiazole / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018757:GABA Modulators / Q000494:pharmacology*; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D010424:Pentobarbital / Q000494:pharmacology; D010852:Picrotoxin / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects*; D012640:Seizures / Q000503:physiopathology / Q000517:prevention & control; D054830:Sesterterpenes; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D002719:Chlormethiazole; D018757:GABA Modulators; D006993:Hypnotics and Sedatives; D010424:Pentobarbital; D010852:Picrotoxin; D011963:Receptors, GABA-A; D054830:Sesterterpenes; D014230:Triazoles; C066440:loreclezole; C037476:tert-butylbicyclophosphorothionate; C022961:picrotoxinin