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 GABAAreceptor.[1] 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 binding affinity for this receptor subtype, with its efficacy as an inverse agonist being around the same at all the subtypes it binds to.[2]
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,[3] 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.[4][5]
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.[6] However it was found to be anxiogenic at doses which enhanced cognition,[7] 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. Still, L-655,708 may find use in the clinic to combat postoperative cognitive dysfunction since administration of sub-nootropic doses of L-655,708 prevented persistent memory impairment in mice anesthetized with isoflurane.[8]
^Quirk K, Blurton P, Fletcher S, Leeson P, Tang F, Mellilo D, et al. (1996). "[3H]L-655,708, a novel ligand selective for the benzodiazepine site of GABAA receptors which contain the alpha 5 subunit". Neuropharmacology. 35 (9–10): 1331–5. doi:10.1016/S0028-3908(96)00061-5. PMID 9014149. S2CID 21608179.
^Casula MA, Bromidge FA, Pillai GV, Wingrove PB, Martin K, Maubach K, et al. (April 2001). "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. 77 (2): 445–51. doi:10.1046/j.1471-4159.2001.00289.x. PMID 11299307. S2CID 84325916.
^Sur C, Fresu L, Howell O, McKernan RM, Atack JR (March 1999). "Autoradiographic localization of alpha5 subunit-containing GABAA receptors in rat brain". Brain Research. 822 (1–2): 265–70. doi:10.1016/S0006-8993(99)01152-X. PMID 10082908. S2CID 54351270.
^Chambers MS, Atack JR, Broughton HB, Collinson N, Cook S, Dawson GR, et al. (May 2003). "Identification of a novel, selective GABA(A) alpha5 receptor inverse agonist which enhances cognition". Journal of Medicinal Chemistry. 46 (11): 2227–40. doi:10.1021/jm020582q. PMID 12747794.
^Chambers MS, Atack JR, Carling RW, Collinson N, Cook SM, Dawson GR, et al. (November 2004). "An orally bioavailable, functionally selective inverse agonist at the benzodiazepine site of GABAA alpha5 receptors with cognition enhancing properties". Journal of Medicinal Chemistry. 47 (24): 5829–32. doi:10.1021/jm040863t. PMID 15537339.
^Atack JR, Bayley PJ, Seabrook GR, Wafford KA, McKernan RM, Dawson GR (November 2006). "L-655,708 enhances cognition in rats but is not proconvulsant at a dose selective for alpha5-containing GABAA receptors". Neuropharmacology. 51 (6): 1023–9. doi:10.1016/j.neuropharm.2006.04.018. PMID 17046030. S2CID 2549642.
^Navarro JF, Burón E, Martín-López M (December 2002). "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 Neuro-Psychopharmacology & Biological Psychiatry. 26 (7–8): 1389–92. doi:10.1016/S0278-5846(02)00305-6. PMID 12502028. S2CID 53188364.
^Saab BJ, Maclean AJ, Kanisek M, Zurek AA, Martin LJ, Roder JC, Orser BA (November 2010). "Short-term memory impairment after isoflurane in mice is prevented by the α5 γ-aminobutyric acid type A receptor inverse agonist L-655,708". Anesthesiology. 113 (5): 1061–71. doi:10.1097/ALN.0b013e3181f56228. PMID 20966663.
^Fischell J, Van Dyke AM, Kvarta MD, LeGates TA, Thompson SM (October 2015). "Rapid Antidepressant Action and Restoration of Excitatory Synaptic Strength After Chronic Stress by Negative Modulators of Alpha5-Containing GABAA Receptors". Neuropsychopharmacology. 40 (11): 2499–509. doi:10.1038/npp.2015.112. PMC4569955. PMID 25900119.
November 08, 2023
8094, nootropic, drug, invented, 1996, team, working, merck, sharp, dohme, that, first, compound, developed, which, acts, subtype, selective, inverse, agonist, subtype, benzodiazepine, binding, site, gabaa, receptor, acts, inverse, agonist, subtypes, with, muc. 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 a5 subtype of the benzodiazepine binding site on the GABAA receptor 1 It acts as an inverse agonist at the a1 a2 a3 and a5 subtypes but with much higher affinity for a5 and unlike newer a5 inverse agonists such as a5IA L 655 708 exerts its subtype selectivity purely via higher binding affinity for this receptor subtype with its efficacy as an inverse agonist being around the same at all the subtypes it binds to 2 L 655 708IdentifiersIUPAC name ethyl 13aS 7 methoxy 9 oxo 11 12 13 13a tetrahydro 9H imidazo 1 5 a pyrrolo 2 1 c 1 4 benzodiazepine 1 carboxylateCAS Number130477 52 0 NPubChem CID5311203ChemSpider4470723 NUNIIL4BX842T8CChEMBLChEMBL52030 NChemical and physical dataFormulaC 18H 19N 3O 4Molar mass341 367 g mol 13D model JSmol Interactive imageSMILES CCOC O c1c2n cn1 c3ccc cc3C O N4 C H 2CCC4 OCInChI InChI 1S C18H19N3O4 c1 3 25 18 23 15 16 14 5 4 8 20 14 17 22 12 9 11 24 2 6 7 13 12 21 16 10 19 15 h6 7 9 10 14H 3 5 8H2 1 2H3 t14 m0 s1 NKey YKYOQIXTECBVBB AWEZNQCLSA N N N Y what is this verify A radiolabelled form of L 655 708 was used to map the distribution of the GABAA a5 subtype in the brain and it was found to be expressed predominantly in the hippocampus 3 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 4 5 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 6 However it was found to be anxiogenic at doses which enhanced cognition 7 most likely because of its inverse agonist effects on other subtypes such as a2 and a3 making it unlikely that this drug would be suitable for use as a nootropic in humans Still L 655 708 may find use in the clinic to combat postoperative cognitive dysfunction since administration of sub nootropic doses of L 655 708 prevented persistent memory impairment in mice anesthetized with isoflurane 8 A study from 2015 found that L 655 708 and another a5 subunit containing GABAA receptor selective negative allosteric modulator MRK 016 produced rapid ketamine like antidepressant effects in animal models of depression 9 See also editGABAA receptor negative allosteric modulator GABAA receptor LigandsReferences edit Quirk K Blurton P Fletcher S Leeson P Tang F Mellilo D et al 1996 3H L 655 708 a novel ligand selective for the benzodiazepine site of GABAA receptors which contain the alpha 5 subunit Neuropharmacology 35 9 10 1331 5 doi 10 1016 S0028 3908 96 00061 5 PMID 9014149 S2CID 21608179 Casula MA Bromidge FA Pillai GV Wingrove PB Martin K Maubach K et al April 2001 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 77 2 445 51 doi 10 1046 j 1471 4159 2001 00289 x PMID 11299307 S2CID 84325916 Sur C Fresu L Howell O McKernan RM Atack JR March 1999 Autoradiographic localization of alpha5 subunit containing GABAA receptors in rat brain Brain Research 822 1 2 265 70 doi 10 1016 S0006 8993 99 01152 X PMID 10082908 S2CID 54351270 Chambers MS Atack JR Broughton HB Collinson N Cook S Dawson GR et al May 2003 Identification of a novel selective GABA A alpha5 receptor inverse agonist which enhances cognition Journal of Medicinal Chemistry 46 11 2227 40 doi 10 1021 jm020582q PMID 12747794 Chambers MS Atack JR Carling RW Collinson N Cook SM Dawson GR et al November 2004 An orally bioavailable functionally selective inverse agonist at the benzodiazepine site of GABAA alpha5 receptors with cognition enhancing properties Journal of Medicinal Chemistry 47 24 5829 32 doi 10 1021 jm040863t PMID 15537339 Atack JR Bayley PJ Seabrook GR Wafford KA McKernan RM Dawson GR November 2006 L 655 708 enhances cognition in rats but is not proconvulsant at a dose selective for alpha5 containing GABAA receptors Neuropharmacology 51 6 1023 9 doi 10 1016 j neuropharm 2006 04 018 PMID 17046030 S2CID 2549642 Navarro JF Buron E Martin Lopez M December 2002 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 Neuro Psychopharmacology amp Biological Psychiatry 26 7 8 1389 92 doi 10 1016 S0278 5846 02 00305 6 PMID 12502028 S2CID 53188364 Saab BJ Maclean AJ Kanisek M Zurek AA Martin LJ Roder JC Orser BA November 2010 Short term memory impairment after isoflurane in mice is prevented by the a5 g aminobutyric acid type A receptor inverse agonist L 655 708 Anesthesiology 113 5 1061 71 doi 10 1097 ALN 0b013e3181f56228 PMID 20966663 Fischell J Van Dyke AM Kvarta MD LeGates TA Thompson SM October 2015 Rapid Antidepressant Action and Restoration of Excitatory Synaptic Strength After Chronic Stress by Negative Modulators of Alpha5 Containing GABAA Receptors Neuropsychopharmacology 40 11 2499 509 doi 10 1038 npp 2015 112 PMC 4569955 PMID 25900119 Retrieved from https en wikipedia org w index php title L 655 708 amp oldid 1158015168, wikipedia, wiki, book, books, library,
