L-655,708 Explained

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 GABA_A 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]

A radiolabelled form of L-655,708 was used to map the distribution of the GABA_A 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 GABA_A receptor-selective negative allosteric modulator, MRK-016, produced rapid, ketamine-like antidepressant effects in animal models of depression.^[9]

See also

• GABA_A receptor negative allosteric modulator
• GABA_A receptor § Ligands

Notes and References

1. Quirk K, Blurton P, Fletcher S, Leeson P, Tang F, Mellilo D, Ragan CI, McKernan RM . 6 . [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 . 1996 . 9014149 . 10.1016/S0028-3908(96)00061-5 . 21608179 .
2. Casula MA, Bromidge FA, Pillai GV, Wingrove PB, Martin K, Maubach K, Seabrook GR, Whiting PJ, Hadingham KL . 6 . 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 . April 2001 . 11299307 . 10.1046/j.1471-4159.2001.00289.x . 84325916 .
3. Sur C, Fresu L, Howell O, McKernan RM, Atack JR . Autoradiographic localization of alpha5 subunit-containing GABAA receptors in rat brain . Brain Research . 822 . 1–2 . 265–70 . March 1999 . 10082908 . 10.1016/S0006-8993(99)01152-X . 54351270 .
4. Chambers MS, Atack JR, Broughton HB, Collinson N, Cook S, Dawson GR, Hobbs SC, Marshall G, Maubach KA, Pillai GV, Reeve AJ, MacLeod AM . 6 . Identification of a novel, selective GABA(A) alpha5 receptor inverse agonist which enhances cognition . Journal of Medicinal Chemistry . 46 . 11 . 2227–40 . May 2003 . 12747794 . 10.1021/jm020582q .
5. 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 . 6 . 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 . November 2004 . 15537339 . 10.1021/jm040863t .
6. 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 . 51 . 6 . 1023–9 . November 2006 . 17046030 . 10.1016/j.neuropharm.2006.04.018 . 2549642 .
7. 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 Neuro-Psychopharmacology & Biological Psychiatry . 26 . 7–8 . 1389–92 . December 2002 . 12502028 . 10.1016/S0278-5846(02)00305-6 . 53188364 .
8. Saab BJ, Maclean AJ, Kanisek M, Zurek AA, Martin LJ, Roder JC, Orser BA . 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 . November 2010 . 20966663 . 10.1097/ALN.0b013e3181f56228 . free .
9. Fischell J, Van Dyke AM, Kvarta MD, LeGates TA, Thompson SM . 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 . October 2015 . 25900119 . 4569955 . 10.1038/npp.2015.112 .