Loreclezole is a sedative and an anticonvulsant which acts as a GABAA receptor positive allosteric modulator .[1] valerenic acid , an extract of the root of the valerian plant.[2] [3] benzodiazepines . A potential benzodiazepine-like interaction with GABA receptors is suggested by the observation that the anticonvulsant effects of loreclezole can be reversed by benzodiazepine receptor inverse agonists. The benzodiazepine antagonist flumazenil, however, fails to alter the anticonvulsant activity of loreclezole, indicating that loreclezole is not a benzodiazepine receptor agonist. Using native rat and cloned human GABA-A receptors, loreclezole strongly potentiated GABA-activated chloride current. However, activity of the drug did not require the presence of the γ-subunit and was not blocked by flumazenil, confirming that loreclezole does not interact with the benzodiazepine recognition site.
References [ edit ]
^ Wingrove, P. B.; Wafford, K. A.; Bain, C.; Whiting, P. J. (1994). "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" . Proceedings of the National Academy of Sciences of the United States of America . 91 (10): 4569–4573. doi :10.1073/pnas.91.10.4569 . PMC 43827 PMID 8183949 . ^ Khom, S.; Baburin, I.; Timin, E.; Hohaus, A.; Trauner, G.; Kopp, B.; Hering, S. (2007). "Valerenic acid potentiates and inhibits GABAA receptors: Molecular mechanism and subunit specificity". Neuropharmacology . 53 (1): 178–187. doi :10.1016/j.neuropharm.2007.04.018 . PMID 17585957 . ^ Rogawski, M (1996). "Epilepsy" . In Pullan, L; Patel, J. Neurotherapeutics: Emerging Strategies . Humana Press. pp. 193–273.
Receptor (ligands )
Agonists
PAMs
(Abridged; see here for a full list) : α-EMTBL Alcohols (e.g., ethanol )Anabolic steroids Avermectins (e.g., ivermectin )Barbiturates (e.g., phenobarbital )Benzodiazepines (e.g., diazepam )Bromide compounds (e.g., potassium bromide )Carbamates (e.g., meprobamate )Carbamazepine Chloralose Chlormezanone Clomethiazole Dihydroergolines (e.g., ergoloid (dihydroergotoxine) )Etazepine Etifoxine Fenamates (e.g., mefenamic acid )Flavonoids (e.g., apigenin , hispidulin )Fluoxetine Flupirtine Imidazoles (e.g., etomidate )Kava constituents (e.g., kavain )Lanthanum Loreclezole Monastrol Neuroactive steroids (e.g., allopregnanolone , cholesterol )Niacin Nicotinamide (niacinamide) Nonbenzodiazepines (e.g., β-carbolines (e.g., abecarnil ), cyclopyrrolones (e.g., zopiclone ), imidazopyridines (e.g., zolpidem ), pyrazolopyrimidines (e.g., zaleplon ))Norfluoxetine Petrichloral Phenols (e.g., propofol )Phenytoin Piperidinediones (e.g., glutethimide )Propanidid Pyrazolopyridines (e.g., etazolate )Quinazolinones (e.g., methaqualone )Retigabine (ezogabine) ROD-188 Skullcap constituents (e.g., baicalin )Stiripentol Sulfonylalkanes (e.g., sulfonmethane (sulfonal) )Topiramate Valerian constituents (e.g., valerenic acid )Volatiles /gases (e.g., chloral hydrate , chloroform , diethyl ether , paraldehyde , sevoflurane )
Antagonists
NAMs
1,3M1B 3M2B 11-Ketoprogesterone 17-Phenylandrostenol α5IA (LS-193,268) β-CCB β-CCE β-CCM β-CCP β-EMGBL Anabolic steroids Amiloride Anisatin β-Lactams (e.g., penicillins , cephalosporins , carbapenems )Basmisanil Bemegride Bilobalide CHEB Cicutoxin Cloflubicyne Cyclothiazide DHEA DHEA-S Dieldrin (+)-DMBB DMCM DMPC EBOB Etbicyphat FG-7142 (ZK-31906) Fiproles (e.g., fipronil )Flavonoids (e.g., amentoflavone , oroxylin A )Flumazenil Fluoroquinolones (e.g., ciprofloxacin )Flurothyl Furosemide Iomazenil (123 I) Isoallopregnanolone Isopregnanolone (sepranolone) L-655,708 Laudanosine Leptazol Lindane MaxiPost Morphine Morphine-3-glucuronide MRK-016 Naloxone Naltrexone Nicardipine Non-steroidal antiandrogens (e.g., apalutamide , bicalutamide , enzalutamide , flutamide , nilutamide )Oenanthotoxin Pentetrazol (metrazol) Phenylsilatrane Picrotoxin (i.e., picrotin and picrotoxinin )Pregnenolone sulfate Propybicyphat PWZ-029 Radequinil Ro 15-4513 Ro 19-4603 RO4882224 RO4938581 Sarmazenil SCS Suritozole TB-21007 TBOB TBPS TCS-1105 Terbequinil TETS Thujone U-93631 Zinc ZK-93426
Agonists
PAMs
Antagonists
NAMs
Agonists
Antagonists
NAMs
PAMs
Transporter (blockers )
Enzyme (inhibitors )
Others
Precursors
Analogues
Others
Alcohols
Barbiturates
Benzodiazepines
Carbamates
Flavonoids
Imidazoles
Kava constituents
Monoureides
Neuroactive steroids
Nonbenzodiazepines
Phenols
Piperidinediones
Pyrazolopyridines
Quinazolinones
Volatiles /gases
Others/unsorted
3-Hydroxybutanal α-EMTBL AA-29504 Avermectins (e.g., ivermectin )Bromide compounds (e.g., lithium bromide , potassium bromide , sodium bromide )Carbamazepine Chloralose Chlormezanone Clomethiazole DEABL Dihydroergolines (e.g., dihydroergocryptine , dihydroergosine , dihydroergotamine , ergoloid (dihydroergotoxine) )DS2 Efavirenz Etazepine Etifoxine Fenamates (e.g., flufenamic acid , mefenamic acid , niflumic acid , tolfenamic acid )Fluoxetine Flupirtine Hopantenic acid Lanthanum Lavender oil Lignans (e.g., 4-O-methylhonokiol , honokiol , magnolol , obovatol )Loreclezole Menthyl isovalerate (validolum) Monastrol Niacin Nicotinamide (niacinamide) Org 25,435 Phenytoin Propanidid Retigabine (ezogabine) Safranal Seproxetine Stiripentol Sulfonylalkanes (e.g., sulfonmethane (sulfonal) , tetronal , trional )Terpenoids (e.g., borneol )Topiramate Valerian constituents (e.g., isovaleric acid , isovaleramide , valerenic acid , valerenol )Unsorted benzodiazepine site PAMs: MRK-409 (MK-0343) TCS-1105 TCS-1205
. PMID 8183949.
