α5IA

α₅IA

Clinical data
ATC code	none
Identifiers
IUPAC name 3-​(5-​methylisoxazol-​3-​yl)-​6-​[(1-​methyl-​1H-​1,2,3-​triazol-​4-​yl)​methoxy]​[1,2,4]triazolo​[3,4-​a]phthalazine
CAS Number	215874-86-5
PubChem (CID)	6918451
ChemSpider	5293648
Chemical and physical data
Formula	C17H14N8O2
Molar mass	362.345 g/mol
3D model (Jmol)	Interactive image
SMILES c4n(C)nnc4COc5c1ccccc1c2nnc(n2n5)-c(c3)noc3C

α₅IA (LS-193,268) is a nootropic drug invented in 2004 by a team working for Merck, Sharp and Dohme, which acts as a subtype-selective inverse agonist at the benzodiazepine binding site on the GABA_A receptor. It binds to the α₁, α₂, α₃ and α₅ subtypes, but shows much higher efficacy at the α₅ subtype, and acts either as a weak partial agonist or inverse agonist at the other subtypes, with its partial agonist effect at α₂ likely to be responsible for the lack of anxiety produced by this drug when compared to older α₅-preferring inverse agonists such as L-655,708.^[1][2]

The α₅ subtype is expressed predominantly in the hippocampus, an area of the brain involved with learning and memory, and activation of this subtype is thought to be largely responsible for producing the cognitive side effects displayed by many benzodiazepine and nonbenzodiazepine drugs, such as amnesia and difficulties with learning and memory. This led researchers to conclude that a drug acting as an inverse agonist at this subtype should have the opposite effect and enhance learning and memory.^[3][4]

Older non-selective inverse agonists at the benzodiazepine site such as DMCM are associated with a range of other effects including anxiety and convulsions, but because α₅IA acts specifically at the α₅ subtype it produces nootropic effects in animal studies, yet without any significant anxiogenic or pro-convulsant effects. This gives α₅IA the potential to be a useful drug either to be used alongside benzodiazepines to counteract their cognitive side effects, or by itself as a nootropic with possible applications in the treatment of Alzheimer's disease and other forms of dementia.^[5][6]

See also

• Basmisanil
• L-655,708
• PWZ-029
• Ro4938581
• TB-21007
• L-838,417

References

1. Sternfeld, F.; Carling, R. W.; Jelley, R. A.; Ladduwahetty, T.; Merchant, K. J.; Moore, K. W.; Reeve, A. J.; Street, L. J.; O'Connor, D.; Sohal, B.; Atack, J. R.; Cook, S.; Seabrook, G.; Wafford, K.; Tattersall, F. D.; Collinson, N.; Dawson, G. R.; Castro, J. L.; MacLeod, A. M. (2004). "Selective, Orally Active γ-Aminobutyric AcidAα5 Receptor Inverse Agonists as Cognition Enhancers". Journal of Medicinal Chemistry. 47 (9): 2176–2179. doi:10.1021/jm031076j. PMID 15084116.
2. Street, L. J.; Sternfeld, F.; Jelley, R. A.; Reeve, A. J.; Carling, R. W.; Moore, K. W.; McKernan, R. M.; Sohal, B.; Cook, S.; Pike, A.; Dawson, G. R.; Bromidge, F. A.; Wafford, K. A.; Seabrook, G. R.; Thompson, S. A.; Marshall, G.; Pillai, G. V.; Castro, J. L.; Atack, J. R.; MacLeod, A. M. (2004). "Synthesis and Biological Evaluation of 3-Heterocyclyl-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo\3,4-a]phthalazines and Analogues as Subtype-Selective Inverse Agonists for the GABAAα5 Benzodiazepine Binding Site". Journal of Medicinal Chemistry. 47 (14): 3642–3657. doi:10.1021/jm0407613. PMID 15214791.
3. Chambers, M. S.; Atack, J. R.; Broughton, H. B.; Collinson, N.; Cook, S.; Dawson, G. R.; Hobbs, S. C.; Marshall, G.; Maubach, K. A.; Pillai, G. V.; Reeve, A. J.; MacLeod, A. M. (2003). "Identification of a Novel, Selective GABAAα5 Receptor Inverse Agonist Which Enhances Cognition". Journal of Medicinal Chemistry. 46 (11): 2227–2240. doi:10.1021/jm020582q. PMID 12747794.
4. Chambers, M. S.; Atack, J. R.; Carling, R. W.; Collinson, N.; Cook, S. M.; Dawson, G. R.; Ferris, P.; Hobbs, S. C.; O'Connor, D.; Marshall, G.; Rycroft, W.; MacLeod, A. M. (2004). "An Orally Bioavailable, Functionally Selective Inverse Agonist at the Benzodiazepine Site of GABAAα5 Receptors with Cognition Enhancing Properties". Journal of Medicinal Chemistry. 47 (24): 5829–5832. doi:10.1021/jm040863t. PMID 15537339.
5. Dawson, G. R.; Maubach, K. A.; Collinson, N.; Cobain, M.; Everitt, B. J.; MacLeod, A. M.; Choudhury, H. I.; McDonald, L. M.; Pillai, G.; Rycroft, W.; Smith, A. J.; Sternfeld, F.; Tattersall, F. D.; Wafford, K. A.; Reynolds, D. S.; Seabrook, G. R.; Atack, J. R. (2005). "An Inverse Agonist Selective for 5 Subunit-Containing GABAA Receptors Enhances Cognition". Journal of Pharmacology and Experimental Therapeutics. 316 (3): 1335–1345. doi:10.1124/jpet.105.092320. PMID 16326923.
6. Collinson, N.; Atack, J. R.; Laughton, P.; Dawson, G. R.; Stephens, D. N. (2006). "An inverse agonist selective for α5 subunit-containing GABAA receptors improves encoding and recall but not consolidation in the Morris water maze". Psychopharmacology. 188 (4): 619–628. doi:10.1007/s00213-006-0361-z. PMID 16633803.