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Α5ia

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Title: Α5ia  
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Subject: L-655,708, TB-21007, PWZ-029, L-838,417, N4-Chloroacetylcytosine arabinoside
Collection: Gabaa Receptor Negative Allosteric Modulators, Isoxazoles, Nootropics, Phenol Ethers, Phthalazines, Triazoles
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Α5ia

α5IA
Systematic (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
Clinical data
Legal status
?
Identifiers
CAS number
ATC code None
PubChem
ChemSpider
Chemical data
Formula C17H14N8O2 
Mol. mass 362.345 g/mol

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 GABAA 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

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.  
  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.  
  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.  
  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.  
  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.  
  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.  
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