L-838,417 is an anxiolytic 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<sub>A</sub> positive allosteric modulator, acting as a partial agonist at ñ<sub>2</sub>, ñ<sub>3</sub> and ñ<sub>5</sub> subtypes. However, it acts as a negative allosteric modulator at the ñ<sub>1</sub> subtype, and has little affinity for the ñ<sub>4</sub> or ñ<sub>6</sub> subtypes. This gives it selective anxiolytic effects, which are mediated mainly by ñ<sub>2</sub> and ñ<sub>3</sub> subtypes, but with little sedative or amnestic effects as these effects are mediated by ñ<sub>1</sub>. Some sedation might still be expected due to its activity at the ñ<sub>5</sub> 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 ñ<sub>2</sub> and ñ<sub>3</sub> subtypes with the ñ<sub>5</sub> 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 imidazopyridine drug zolpidem. 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<sub>A</sub> receptor subtypes (i.e. ñ<sub>2</sub>, ñ<sub>3</sub>) and restoring Cl<sup>âÂÂ</sup> homeostasis.