Α5IA

drugbox
IUPAC_name = 3-(5-methylisoxazol-3-yl)-6- [(1-methyl-1,2,3-triazol-4-yl)methyloxy] -1,2,4-triazolo [3,4-a] phthalazine


imagename = α5IA
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PubChem = 6918451
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C=17|H=14|N=8|O=2
molecular_weight = 362.345 g/mol
smiles = c4n(C)nnc4COc5c1ccccc1c2nnc(n2n5)-c(c3)noc3C
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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. [Sternfeld F, Carling RW, Jelley RA, Ladduwahetty T, Merchant KJ, Moore KW, Reeve AJ, Street LJ, O'Connor D, Sohal B, Atack JR, Cook S, Seabrook G, Wafford K, Tattersall FD, Collinson N, Dawson GR, Castro JL, MacLeod AM. Selective, orally active gamma-aminobutyric acidA alpha5 receptor inverse agonists as cognition enhancers. "Journal of Medicinal Chemistry". 2004 Apr 22;47(9):2176-9. PMID 15084116] [Street LJ, Sternfeld F, Jelley RA, Reeve AJ, Carling RW, Moore KW, McKernan RM, Sohal B, Cook S, Pike A, Dawson GR, Bromidge FA, Wafford KA, Seabrook GR, Thompson SA, Marshall G, Pillai GV, Castro JL, Atack JR, MacLeod AM. 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 GABA(A)alpha5 benzodiazepine binding site. "Journal of Medicinal Chemistry". 2004 Jul 1;47(14):3642-57. PMID 15214791]

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. [Chambers MS, Atack JR, Broughton HB, Collinson N, Cook S, Dawson GR, Hobbs SC, Marshall G, Maubach KA, Pillai GV, Reeve AJ, MacLeod AM. Identification of a novel, selective GABA(A) alpha5 receptor inverse agonist which enhances cognition. "Journal of Medicinal Chemistry". 2003 May 22;46(11):2227-40. PMID 12747794] [Chambers MS, Atack JR, Carling RW, Collinson N, Cook SM, Dawson GR, Ferris P, Hobbs SC, O'connor D, Marshall G, Rycroft W, Macleod AM. An orally bioavailable, functionally selective inverse agonist at the benzodiazepine site of GABAA alpha5 receptors with cognition enhancing properties. "Journal of Medicinal Chemistry". 2004 Nov 18;47(24):5829-32. PMID 15537339]

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. [Dawson GR, Maubach KA, Collinson N, Cobain M, Everitt BJ, MacLeod AM, Choudhury HI, McDonald LM, Pillai G, Rycroft W, Smith AJ, Sternfeld F, Tattersall FD, Wafford KA, Reynolds DS, Seabrook GR, Atack JR. An inverse agonist selective for alpha5 subunit-containing GABAA receptors enhances cognition. "Journal of Pharmacology and Experimental Therapeutics". 2006 Mar;316(3):1335-45. PMID 16326923] [Collinson N, Atack JR, Laughton P, Dawson GR, Stephens DN. An inverse agonist selective for alpha5 subunit-containing GABAA receptors improves encoding and recall but not consolidation in the Morris water maze. "Psychopharmacology (Berlin)". 2006 Nov;188(4):619-28. PMID 16633803]

References