L-838,417

L-838,417
Ball-and-stick model of the L-838,417 molecule
Identifiers
  • 3-(2,5-Difluorophenyl)-7-(1,1-dimethylethyl)-6-[(1-methyl-1H-1,2,4-triazol-5-yl)methoxy]-1,2,4-triazolo[4,3-b]pyridazine
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC19H19F2N7O
Molar mass399.406 g·mol−1
3D model (JSmol)
  • CN1N=CN=C1COC4=NN2C(C=C4C(C)(C)C)=NN=C2C3=CC(F)=CC=C3F
  • InChI=1S/C19H19F2N7O/c1-19(2,3)13-8-15-24-25-17(12-7-11(20)5-6-14(12)21)28(15)26-18(13)29-9-16-22-10-23-27(16)4/h5-8,10H,9H2,1-4H3 checkY
  • Key:BQDUNOMMYOKHEP-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

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 GABAA positive allosteric modulator, acting as a partial agonist 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.[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] The synthesis of L-838,417 and similar compounds was described in 2005 in the Journal of Medicinal Chemistry.[8]

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 GABAA receptor subtypes (i.e. α2, α3) and restoring Cl− homeostasis.[9]

  1. ^ 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. PMID 10816315. S2CID 10340592.
  2. ^ 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. PMID 15926867. S2CID 22793644.
  3. ^ 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. PMID 16706856. S2CID 24380865.
  4. ^ 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. PMID 17426483. S2CID 7867324.
  5. ^ 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. PMID 17113111. S2CID 11504408.
  6. ^ 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. PMID 16339395. S2CID 21913400.
  7. ^ 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. PMID 16133136. S2CID 8312733.
  8. ^ 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. PMID 16279764.
  9. ^ Lorenzo LE, Godin AG, Ferrini F, Bachand K, Plasencia-Fernandez I, Labrecque S, et al. (February 2020). "A-mediated analgesia in neuropathic pain". Nature Communications. 11 (1): 869. Bibcode:2020NatCo..11..869L. doi:10.1038/s41467-019-14154-6. PMC 7018745. PMID 32054836.