IUPAC_name = ethyl-7-methoxy-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine-1-carboxylate

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PubChem = 5311203
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molecular_weight = 341.360 g/mol
smiles = CCOC(=O)c2ncn-1c2C3CCCN3C(=O)c(c4)c-1ccc4OC
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L-655,708 (FG-8094) is a nootropic drug invented in 1996 by a team working for Merck, Sharp and Dohme, that was the first compound developed which acts as a subtype-selective inverse agonist at the α5 subtype of the benzodiazepine binding site on the GABAA receptor. [Quirk K, Blurton P, Fletcher S, Leeson P, Tang F, Mellilo D, Ragan CI, McKernan RM. [3H] L-655,708, a novel ligand selective for the benzodiazepine site of GABAA receptors which contain the alpha 5 subunit. "Neuropharmacology". 1996;35(9-10):1331-5. PMID 9014149] It acts as an inverse agonist at the α1, α2, α3 and α5 subtypes, but with much higher affinity for α5, and unlike newer α5 inverse agonists such as α5IA, L-655,708 exerts its subtype selectivity purely via higher affinity for this receptor subtype, with its efficacy as an inverse agonist being around the same at all the subtypes it binds to. [Casula MA, Bromidge FA, Pillai GV, Wingrove PB, Martin K, Maubach K, Seabrook GR, Whiting PJ, Hadingham KL. Identification of amino acid residues responsible for the alpha5 subunit binding selectivity of L-655,708, a benzodiazepine binding site ligand at the GABA(A) receptor. "Journal of Neurochemistry". 2001 Apr;77(2):445-51. PMID 11299307]

A radiolabelled form of L-655,708 was used to map the distribution of the GABAA α5 subtype in the brain, and it was found to be expressed predominantly in the hippocampus, [Sur C, Fresu L, Howell O, McKernan RM, Atack JR. Autoradiographic localization of alpha5 subunit-containing GABAA receptors in rat brain. "Brain Research". 1999 Mar 20;822(1-2):265-70. PMID 10082908] an area of the brain involved with learning and memory. 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, and so 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]

L-655,708 was indeed found to produce improved cognitive performance in animal studies, without producing the side effect of convulsions which is produced by non-selective inverse agonists like DMCM. [Atack JR, Bayley PJ, Seabrook GR, Wafford KA, McKernan RM, Dawson GR. L-655,708 enhances cognition in rats but is not proconvulsant at a dose selective for alpha5-containing GABAA receptors. "Neuropharmacology". 2006 Nov;51(6):1023-9. PMID 17046030] However it was found to be anxiogenic at doses which enhanced cognition, [Navarro JF, Burón E, Martín-López M. Anxiogenic-like activity of L-655,708, a selective ligand for the benzodiazepine site of GABA(A) receptors which contain the alpha-5 subunit, in the elevated plus-maze test. "Progress in Neuropsychopharmacology and Biological Psychiatry". 2002 Dec;26(7-8):1389-92. PMID 12502028] most likely because of its inverse agonist effects on other subtypes such as α2 and α3, making it unlikely that this drug would be suitable for use as a nootropic in humans.


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