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Chemical compound
Ro4938581 is a nootropic drug invented in 2009 by a team working for Hoffmann-La Roche , which acts as a subtype-selective inverse agonist at the α5 subtype of the benzodiazepine binding site on the GABAA receptor . It has good selectivity for the α5 subtype and did not produce convulsant or anxiogenic effects in animal studies, making it a promising potential nootropic.[ 1] [ 2] [ 3] basmisanil (RG-1662, RO5186582) have subsequently been investigated for the alleviation of cognitive dysfunction in Down syndrome .[ 4] [ 5]
^ Ballard TM, Knoflach F, Prinssen E, Borroni E, Vivian JA, Basile J, et al. (January 2009). "RO4938581, a novel cognitive enhancer acting at GABAA alpha5 subunit-containing receptors". Psychopharmacology . 202 (1–3): 207–23. doi :10.1007/s00213-008-1357-7 . PMID 18936916 . S2CID 22011375 . ^ Knust H, Achermann G, Ballard T, Buettelmann B, Gasser R, Fischer H, et al. (October 2009). "The discovery and unique pharmacological profile of RO4938581 and RO4882224 as potent and selective GABAA alpha5 inverse agonists for the treatment of cognitive dysfunction". Bioorganic & Medicinal Chemistry Letters . 19 (20): 5940–4. doi :10.1016/j.bmcl.2009.08.053 . PMID 19762240 . ^ Redrobe JP, Elster L, Frederiksen K, Bundgaard C, de Jong IE, Smith GP, et al. (June 2012). "Negative modulation of GABAA α5 receptors by RO4938581 attenuates discrete sub-chronic and early postnatal phencyclidine (PCP)-induced cognitive deficits in rats". Psychopharmacology . 221 (3): 451–68. doi :10.1007/s00213-011-2593-9 . PMID 22124672 . S2CID 2550795 . ^ Martínez-Cué C, Martínez P, Rueda N, Vidal R, García S, Vidal V, et al. (February 2013). "Reducing GABAA α5 receptor-mediated inhibition rescues functional and neuromorphological deficits in a mouse model of down syndrome" . The Journal of Neuroscience . 33 (9): 3953–66. doi :10.1523/JNEUROSCI.1203-12.2013 . PMC 6619314 PMID 23447605 . ^ Breindl A (2019). "Inhibiting Inhibition to Treat Down Syndrome Symptoms" . BioWorld .
Ionotropic
GABAA Tooltip γ-Aminobutyric acid A receptor
Positive modulators (abridged; see here for a full list): α-EMTBL Alcohols (e.g., drinking alcohol , 2M2B )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 , THDOC )Niacin 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 )Negative modulators: 1,3M1B 3M2B 11-Ketoprogesterone 17-Phenylandrostenol α3IA 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 Bicyclic phosphates (TBPS , TBPO , IPTBO )BIDN Bilobalide Bupropion CHEB Chlorophenylsilatrane 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 Golexanolone Iomazenil (123 I) IPTBO Isopregnanolone (sepranolone) L-655,708 Laudanosine Lindane MaxiPost Morphine Morphine-3-glucuronide MRK-016 Naloxone Naltrexone Nicardipine Nonsteroidal antiandrogens (e.g., apalutamide , bicalutamide , enzalutamide , flutamide , nilutamide )Oenanthotoxin Pentylenetetrazol (pentetrazol) Phenylsilatrane Picrotoxin (i.e., picrotin , picrotoxinin and dihydropicrotoxinin )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 GABAA -ρ Tooltip γ-Aminobutyric acid A-rho receptor
Metabotropic
GABAB Tooltip γ-Aminobutyric acid B receptor
