L-655,708

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.[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]

L-655,708
Identifiers
IUPAC 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-carboxylate
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
Chemical and physical data
FormulaC18H19N3O4
Molar mass341.367 g·mol−1
3D model (JSmol)
SMILES
  • CCOC(=O)c1c2n(cn1)-c3ccc(cc3C(=O)N4[C@H]2CCC4)OC
InChI
  • 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 N
  • Key:YKYOQIXTECBVBB-AWEZNQCLSA-N N
 NY (what is this?)  (verify)

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]

A study from 2015 found that L-655,708, and another α5 subunit-containing GABAA receptor-selective negative allosteric modulator, MRK-016, produced rapid, ketamine-like antidepressant effects in animal models of depression.[9]

See also

References
  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
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