L-838,417 is an

anxiolytic An anxiolytic (; also antipanic or antianxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxiet ...

drug used in scientific research. It has similar effects to benzodiazepine drugs, but is structurally distinct and so is classed as a nonbenzodiazepine anxiolytic. The compound was developed by Merck, Sharp and Dohme. L-838,417 is a subtype-selective GABA_A

positive 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 to ...

, acting as a

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. They may also be considered ligands which display both agonistic and antagonis ...

at α₂, α₃ and α₅ subtypes. However, it acts as a

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 ...

at the α₁ subtype, and has little affinity for the α₄ or α₆ subtypes. This gives it selective

effects, which are mediated mainly by α₂ and α₃ subtypes, but with little sedative or

amnestic Amnesia is a deficit in memory caused by brain damage or disease,Gazzaniga, M., Ivry, R., & Mangun, G. (2009) Cognitive Neuroscience: The biology of the mind. New York: W.W. Norton & Company. but it can also be caused temporarily by the use o ...

effects as these effects are mediated by α₁. Some sedation might still be expected due to its activity at the α₅ subtype, which can also cause sedation, however no sedative effects were seen in animal studies even at high doses, suggesting that L-838,417 is primarily acting at α₂ and α₃ subtypes with the α₅ subtype of lesser importance. As might be predicted from its binding profile, L-838,417 substitutes for the anxiolytic benzodiazepine

chlordiazepoxide Chlordiazepoxide, trade name Librium among others, is a sedative and hypnotic medication of the benzodiazepine class; it is used to treat anxiety, insomnia and symptoms of withdrawal from alcohol and other drugs. Chlordiazepoxide has a medium t ...

in animals, but not for the hypnotic

imidazopyridine An imidazopyridine is a nitrogen containing heterocycle that is also a class of drugs that contain this same chemical substructure. In general, they are GABAA receptor agonists, however recently proton pump inhibitors, aromatase inhibitors, NSA ...

drug

zolpidem Zolpidem, sold under the brand name Ambien, among others, is a medication primarily used for the short-term treatment of sleeping problems. Guidelines recommend that it be used only after cognitive behavioral therapy for insomnia and behavior ...

. The synthesis of L-838,417 and similar compounds was described in 2005 in the

Journal of Medicinal Chemistry A journal, from the Old French ''journal'' (meaning "daily"), may refer to: *Bullet journal, a method of personal organization *Diary, a record of what happened over the course of a day or other period *Daybook, also known as a general journal, a ...

. In neuropathic pain animal models, it has been shown that stabilizing the Potassium Chloride Cotranspoter 2 ( KCC2) at neuronal membranes could not only potentiate the L-838,417-induced analgesia in rats, but also rescue its analgesic potential at high doses, revealing a novel strategy for analgesia in pathological pain, by combined targeting of the appropriate GABA_A receptor subtypes (i.e. α₂, α₃) and restoring Cl⁻ homeostasis.

References

{{GABAAR PAMs Anxiolytics Fluoroarenes Triazolopyridazines Ethers Triazoles GABAA receptor positive allosteric modulators Tert-butyl compounds

See also

References