L-655,708 (FG-8094) is a

nootropic Nootropics ( , or ) (colloquial: smart drugs and cognitive enhancers, similar to adaptogens) are a wide range of natural or synthetic dietary supplement, supplements or drugs and other substances that are claimed to improve cognitive function ...

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 Receptor may refer to: * Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...

. 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 In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from ''ligare'', which means 'to bind'. In protein-ligand binding, the ligand is usually a m ...

for this receptor subtype, with its efficacy as an inverse agonist being around the same at all the subtypes it binds to. A

radiolabelled Isotopic labeling (or isotopic labelling) is a technique used to track the passage of an isotope (an atom with a detectable variation in neutron count) through a reaction, metabolic pathway, or cell. The reactant is 'labeled' by replacing specific ...

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 The hippocampus (via Latin from Greek , ' seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, ...

, 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. 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. However it was found to be anxiogenic at doses which enhanced cognition, 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

in humans. Still, L-655,708 may find use in the clinic to combat

postoperative cognitive dysfunction Postoperative cognitive dysfunction (POCD) is a decline in cognition, cognitive function (especially in memory and executive functions) that may last from 1–12 months after surgery, or longer. In some cases, this disorder may persist for several y ...

since administration of sub-nootropic doses of L-655,708 prevented persistent memory impairment in mice anesthetized with

isoflurane Isoflurane, sold under the brand name Forane among others, is a general anesthetic. It can be used to start or maintain anesthesia; however, other medications are often used to start anesthesia rather than isoflurane, due to airway irritation w ...

. A study from 2015 found that L-655,708, and another α₅ subunit-containing GABA_A receptor-selective

negative allosteric modulator In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimulus. Some of them, like benzodiazepines, are drugs. The site that an allosteric modulator binds t ...

, MRK-016, produced rapid,

ketamine Ketamine is a dissociative anesthetic used medically for induction and maintenance of anesthesia. It is also used as a recreational drug. It is one of the safest anesthetics, as, in contrast with opiates, ether, and propofol, it suppresses ...

-like antidepressant effects in

animal model An animal model (short for animal disease model) is a living, non-human, often genetic-engineered animal used during the research and investigation of human disease, for the purpose of better understanding the disease process without the risk of ha ...

s of depression.

References

{{Benzodiazepines Anxiogenics Carboxylate esters GABAA receptor negative allosteric modulators Imidazopyrrolobenzodiazepines Lactams Nootropics Phenol ethers

See also

References