L-838,417

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.

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L-838,417 is a subtype-selective GABA_A agonist, acting as a partial agonist at α2, α3 and α5 subtypes, but as an antagonist at the α1 subtype, and has little affinity for the α4 or α6 subtypes.^[1] This gives it selective anxiolytic effects, which are mediated mainly by α2 and α3 subtypes, but with little sedative or amnestic effects as these effects are mediated by α1.^[2][3] 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.^[4][5]

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.^[6][7]

References

1. ^ McKernan RM, Rosahl TW, Reynolds DS, Sur C, Wafford KA, Atack JR, Farrar S, Myers J, Cook G, Ferris P, Garrett L, Bristow L, Marshall G, Macaulay A, Brown N, Howell O, Moore KW, Carling RW, Street LJ, Castro JL, Ragan CI, Dawson GR, Whiting PJ. Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype. Nature Neuroscience. 2000 Jun;3(6):587-92.
2. ^ Atack JR. The benzodiazepine binding site of GABA(A) receptors as a target for the development of novel anxiolytics. Expert Opinion on Investigational Drugs. 2005 May;14(5):601-18.
3. ^ Morris HV, Dawson GR, Reynolds DS, Atack JR, Stephens DN. Both alpha2 and alpha3 GABAA receptor subtypes mediate the anxiolytic properties of benzodiazepine site ligands in the conditioned emotional response paradigm. European Journal of Neuroscience. 2006 May;23(9):2495-504.
4. ^ Mathiasen LS, Rodgers RJ, Mirza NR. Comparative effects of nonselective and subtype-selective gamma-aminobutyric acidA receptor positive modulators in the rat-conditioned emotional response test. Behavioural Pharmacology. 2007 May;18(3):191-203.
5. ^ Ujfalussy B, Kiss T, Orbán G, Hoffmann WE, Erdi P, Hajós M. Pharmacological and computational analysis of alpha-subunit preferential GABA(A) positive allosteric modulators on the rat septo-hippocampal activity. Neuropharmacology. 2007 Mar;52(3):733-43.
6. ^ Mirza NR, Rodgers RJ, Mathiasen LS. Comparative cue generalization profiles of L-838, 417, SL651498, zolpidem, CL218,872, ocinaplon, bretazenil, zopiclone, and various benzodiazepines in chlordiazepoxide and zolpidem drug discrimination. Journal of Pharmacology and Experimental Therapeutics. 2006 Mar;316(3):1291-9.
7. ^ Mathiasen L, Mirza NR. A comparison of chlordiazepoxide, bretazenil, L838,417 and zolpidem in a validated mouse Vogel conflict test. Psychopharmacology (Berlin). 2005 Nov;182(4):475-84.