L-838,417 is an

anxiolytic An anxiolytic (; also antipanic or anti-anxiety 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 anxie ...

drug used in scientific research. It has similar effects to

benzodiazepine Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant, depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed t ...

drugs, but is structurally distinct and so is classed as a

nonbenzodiazepine Nonbenzodiazepines (), sometimes referred to colloquially as Z-drugs (as many of their names begin with the letter "z"), are a class of psychoactive, depressant, sedative, hypnotic, anxiolytic drugs that are benzodiazepine-like in uses, such as f ...

anxiolytic. The compound was developed by Merck, Sharp and Dohme. L-838,417 is a subtype-selective GABA_A positive allosteric modulator, acting as a

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given Receptor (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...

at α₂, α₃ and α₅ subtypes. However, it acts as a negative allosteric modulator 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 A sedative or tranquilliser is a substance that induces sedation by reducing irritability or Psychomotor agitation, excitement. They are central nervous system (CNS) Depressant, depressants and interact with brain activity, causing its decelera ...

or amnestic 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 in animals, but not for the

hypnotic A hypnotic (from Ancient Greek, Greek ''Hypnos'', sleep), also known as a somnifacient or soporific, and commonly known as sleeping pills, are a class of psychoactive drugs whose primary function is to sleep induction, induce sleep and to trea ...

imidazopyridine An imidazopyridine is a nitrogen containing heterocycle that is also a class of medication, drugs that contain this same chemical substructure. In general, they are GABAA receptor, GABAA receptor receptor_agonist, agonists, however recently proto ...

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 after beh ...

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