L-838,417 is a subtype-selectiveGABAApositive allosteric modulator, acting as apartial agonist atα2,α3 andα5 subtypes. However, it acts as anegative allosteric modulator at theα1 subtype, and has little affinity for theα4 orα6 subtypes.[1] This gives it selectiveanxiolytic effects, which are mediated mainly by α2 and α3 subtypes, but with littlesedative oramnestic 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]
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 appropriateGABAA receptor subtypes (i.e.α2,α3) and restoring Cl− homeostasis.[9]
^McKernan RM, Rosahl TW, Reynolds DS, Sur C, Wafford KA, Atack JR, et al. (June 2000). "Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype".Nature Neuroscience.3 (6):587–92.doi:10.1038/75761.PMID10816315.S2CID10340592.
^Atack JR (May 2005). "The benzodiazepine binding site of GABA(A) receptors as a target for the development of novel anxiolytics".Expert Opinion on Investigational Drugs.14 (5):601–18.doi:10.1517/13543784.14.5.601.PMID15926867.S2CID22793644.
^Morris HV, Dawson GR, Reynolds DS, Atack JR, Stephens DN (May 2006). "Both alpha2 and alpha3 GABAA receptor subtypes mediate the anxiolytic properties of benzodiazepine site ligands in the conditioned emotional response paradigm".The European Journal of Neuroscience.23 (9):2495–504.doi:10.1111/j.1460-9568.2006.04775.x.PMID16706856.S2CID24380865.
^Mathiasen LS, Rodgers RJ, Mirza NR (May 2007). "Comparative effects of nonselective and subtype-selective gamma-aminobutyric acidA receptor positive modulators in the rat-conditioned emotional response test".Behavioural Pharmacology.18 (3):191–203.doi:10.1097/FBP.0b013e32814fcdd4.PMID17426483.S2CID7867324.
^Ujfalussy B, Kiss T, Orbán G, Hoffmann WE, Erdi P, Hajós M (March 2007). "Pharmacological and computational analysis of alpha-subunit preferential GABA(A) positive allosteric modulators on the rat septo-hippocampal activity".Neuropharmacology.52 (3):733–43.doi:10.1016/j.neuropharm.2006.09.022.PMID17113111.S2CID11504408.
^Mirza NR, Rodgers RJ, Mathiasen LS (March 2006). "Comparative cue generalization profiles of L-838, 417, SL651498, zolpidem, CL218,872, ocinaplon, bretazenil, zopiclone, and various benzodiazepines in chlordiazepoxide and zolpidem drug discrimination".The Journal of Pharmacology and Experimental Therapeutics.316 (3):1291–9.doi:10.1124/jpet.105.094003.PMID16339395.S2CID21913400.
^Mathiasen L, Mirza NR (November 2005). "A comparison of chlordiazepoxide, bretazenil, L838,417 and zolpidem in a validated mouse Vogel conflict test".Psychopharmacology.182 (4):475–84.doi:10.1007/s00213-005-0119-z.PMID16133136.S2CID8312733.
^Carling RW, Madin A, Guiblin A, Russell MG, Moore KW, Mitchinson A, et al. (November 2005). "7-(1,1-Dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine: a functionally selective gamma-aminobutyric acid(A) (GABA(A)) alpha2/alpha3-subtype selective agonist that exhibits potent anxiolytic activity but is not sedating in animal models".Journal of Medicinal Chemistry.48 (23):7089–92.doi:10.1021/jm058034a.PMID16279764.
N
Y (what is this?) (verify)