Ro4938581

Ro4938581
Identifiers
	IUPAC name 3-Bromo-10-(difluoromethyl)-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]diazepine;
CAS Number	883093-10-5 ;
PubChem CID	11624499;
IUPHAR/BPS	4299;
ChemSpider	9799246;
UNII	ZK5NA2M82J;
ChEMBL	ChEMBL1080588;
CompTox Dashboard (EPA)	DTXSID601045378 ;
Chemical and physical data
Formula	C13H8BrF2N5
Molar mass	352.143 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES FC(F)C(N=C1)=C(N1C2=C3C=C(Br)C=C2)CN4C3=NC=N4;
	InChI InChI=1S/C13H8BrF2N5/c14-7-1-2-9-8(3-7)13-17-5-19-21(13)4-10-11(12(15)16)18-6-20(9)10/h1-3,5-6,12H,4H2; Key:AFJRYPJIKHMNGL-UHFFFAOYSA-N;

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 GABA_A 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] Ro4938581 and a related derivative basmisanil (RG-1662, RO5186582) have subsequently been investigated for the alleviation of cognitive dysfunction in Down syndrome.^[4]^[5]

References

^ 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.

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[1] 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.

[2] 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.

[3] 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.

[4] 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.

[5] Breindl A (2019). "Inhibiting Inhibition to Treat Down Syndrome Symptoms". BioWorld.

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v t e Benzodiazepines
1,4-Benzodiazepines	2-Oxoquazepam 3-Hydroxyphenazepam Bromazepam BMS-906024* Camazepam Carburazepam Chlordiazepoxide Cinazepam Cinolazepam Clonazepam Cloniprazepam Clorazepate Cyprazepam Delorazepam Demoxepam Desmethylflunitrazepam Devazepide* Diazepam Diclazepam Difludiazepam Doxefazepam Elfazepam Ethyl carfluzepate Ethyl dirazepate Ethyl loflazepate Flubromazepam Fletazepam Fludiazepam Flunitrazepam Flurazepam Flutemazepam Flutoprazepam Fosazepam Gidazepam Halazepam Iclazepam Irazepine* Kenazepine Ketazolam Lorazepam Lormetazepam Lufuradom* Meclonazepam Medazepam Menitrazepam Metaclazepam Motrazepam N-Desalkylflurazepam Nifoxipam Nimetazepam Nitemazepam Nitrazepam Nitrazepate Nordazepam Nortetrazepam Oxazepam Phenazepam Pinazepam Pivoxazepam Prazepam Proflazepam Quazepam QH-II-66 Reclazepam RO4491533* Ro05-4082 Ro5-4864* Ro07-5220 Ro07-9749 Ro20-8065 Ro20-8552 SH-I-048A Sulazepam Temazepam Tetrazepam Tifluadom* Timelotem* Tolufazepam Triflunordazepam Tuclazepam Uldazepam
1,5-Benzodiazepines	Arfendazam Clobazam CP-1414S Lofendazam Triflubazam
2,3-Benzodiazepines*	Girisopam GYKI-52466 GYKI-52895 Nerisopam Talampanel Tofisopam
Triazolobenzodiazepines	Adinazolam Alprazolam Balovaptan* Bromazolam Clonazolam Estazolam Fluadinazolam Flualprazolam Flubromazolam Flunitrazolam Nitrazolam Phenazolam Pyrazolam Rilmazolam (active metabolite of Rilmazafone) Triazolam
Imidazobenzodiazepines	Bretazenil Climazolam EVT-201 FG-8205 Flumazenil GL-II-73 Imidazenil ¹²³I-Iomazenil L-655,708 Loprazolam Midazolam PWZ-029 Remimazolam Ro15-4513 Ro48-6791 Ro48-8684 Ro4938581 Sarmazenil SH-053-R-CH3-2′F
Oxazolobenzodiazepines	Cloxazolam Flutazolam Haloxazolam Mexazolam Oxazolam
Thienodiazepines	Bentazepam Clotiazepam Ro09-9212
Thienotriazolodiazepines	α-Hydroxyetizolam Apafant* Brotizolam Ciclotizolam Clotizolam Deschloroclotizolam Deschloroetizolam Etizolam Flubrotizolam Fluclotizolam Fluetizolam Israpafant* JQ1* Metizolam
Thienobenzodiazepines*	Olanzapine Telenzepine
Pyridodiazepines	Lopirazepam
Pyridotriazolodiazepines	Zapizolam
Pyrazolodiazepines	Razobazam* Ripazepam Zolazepam Zomebazam Zometapine*
Pyrrolodiazepines	Premazepam
Tetrahydroisoquinobenzodiazepines	Clazolam
Pyrrolobenzodiazepines*	Anthramycin
Benzodiazepine prodrugs	Alprazolam triazolobenzophenone Avizafone Rilmazafone
* atypical activity profile (not GABA_A receptor ligands)

See also

References