α5IA

α₅IA
Clinical data
Other names	LS-193,268
ATC code	None;
Pharmacokinetic data
Elimination half-life	2-2.5h
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;
UNII	1M7NI1A92L;
CompTox Dashboard (EPA)	DTXSID10175950 ;
Chemical and physical data
Formula	C17H14N8O2
Molar mass	362.353 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES CC1=CC(=NO1)C2=NN=C3N2N=C(C4=CC=CC=C43)OCC5=CN(N=N5)C;
	InChI InChI=1S/C17H14N8O2/c1-10-7-14(22-27-10)16-20-19-15-12-5-3-4-6-13(12)17(21-25(15)16)26-9-11-8-24(2)23-18-11/h3-8H,9H2,1-2H3; Key:NZMJFRXKGUCYNP-UHFFFAOYSA-N;

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 α₁, α₂, α₃ and α₅ -containing subtypes, with functional selectivity for α₅-containing subtypes.^[1]^[2]

Clinical research

Administration of α₅IA following alcohol consumption was found to reverse memory impairments induced by alcohol.^[3]

In vitro electrophysiology

Recordings of local field potentials indicate that oral administration of α5IA increases the amplitude of sharp wave ripples which are implicated in memory function in adult wild type rats. The increase in ripple amplitude is not seen in adult male TgF344-AD rats which express human β-amyloid precursor protein (with the Swedish mutation) and human presenilin-1 (with a Δ exon 9 mutation).^[4]

References

^ Sternfeld F, Carling RW, Jelley RA, Ladduwahetty T, Merchant KJ, Moore KW, et al. (April 2004). "Selective, orally active gamma-aminobutyric acidA alpha5 receptor inverse agonists as cognition enhancers". Journal of Medicinal Chemistry. 47 (9): 2176–9. doi:10.1021/jm031076j. PMID 15084116.
^ Street LJ, Sternfeld F, Jelley RA, Reeve AJ, Carling RW, Moore KW, et al. (July 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 GABA(A)alpha5 benzodiazepine binding site". Journal of Medicinal Chemistry. 47 (14): 3642–57. doi:10.1021/jm0407613. PMID 15214791.
^ Atack JR (2008). "GABA(A) receptor subtype-selective efficacy: TPA023, an alpha2/alpha3 selective non-sedating anxiolytic and alpha5IA, an alpha5 selective cognition enhancer". CNS Neuroscience & Therapeutics. 14 (1): 25–35. doi:10.1111/j.1527-3458.2007.00034.x. ISSN 1755-5930. PMC 6494020. PMID 18482097.
^ Ratner MH, Downing SS, Guo O, Odamah KE, Stewart TM, Kumaresan V, et al. (September 2021). "Prodromal dysfunction of α5GABA-A receptor modulated hippocampal ripples occurs prior to neurodegeneration in the TgF344-AD rat model of Alzheimer's disease". Heliyon. 7 (9): e07895. doi:10.1016/j.heliyon.2021.e07895. PMC 8449175. PMID 34568591.

[1] Sternfeld F, Carling RW, Jelley RA, Ladduwahetty T, Merchant KJ, Moore KW, et al. (April 2004). "Selective, orally active gamma-aminobutyric acidA alpha5 receptor inverse agonists as cognition enhancers". Journal of Medicinal Chemistry. 47 (9): 2176–9. doi:10.1021/jm031076j. PMID 15084116.

[2] Street LJ, Sternfeld F, Jelley RA, Reeve AJ, Carling RW, Moore KW, et al. (July 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 GABA(A)alpha5 benzodiazepine binding site". Journal of Medicinal Chemistry. 47 (14): 3642–57. doi:10.1021/jm0407613. PMID 15214791.

[3] Atack JR (2008). "GABA(A) receptor subtype-selective efficacy: TPA023, an alpha2/alpha3 selective non-sedating anxiolytic and alpha5IA, an alpha5 selective cognition enhancer". CNS Neuroscience & Therapeutics. 14 (1): 25–35. doi:10.1111/j.1527-3458.2007.00034.x. ISSN 1755-5930. PMC 6494020. PMID 18482097.

[4] Ratner MH, Downing SS, Guo O, Odamah KE, Stewart TM, Kumaresan V, et al. (September 2021). "Prodromal dysfunction of α5GABA-A receptor modulated hippocampal ripples occurs prior to neurodegeneration in the TgF344-AD rat model of Alzheimer's disease". Heliyon. 7 (9): e07895. doi:10.1016/j.heliyon.2021.e07895. PMC 8449175. PMID 34568591.

[1]

[2]

[3]

[4]

Clinical research

In vitro electrophysiology

See also

References