L-838,417

drugbox
IUPAC_name = 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

---

width = 250px
CAS_number = 286456-42-6
ATC_prefix =
ATC_suffix =
PubChem = 9908880
DrugBank =
C=19|H=19|F=2|N=7|O=1
molecular_weight = 399.397 g/mol
smiles = CN1N=CN=C1COC4=NN2C(C=C4C(C)(C)C)=NN=C2C3=CC(F)=CC=C3F
bioavailability =
protein_bound =
metabolism =
elimination_half-life =
excretion =
pregnancy_AU =
pregnancy_US =
pregnancy_category=
legal_AU =
legal_CA =
legal_UK =
legal_US =
legal_status =
routes_of_administration =

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_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.cite journal
author=McKernan RM, Rosahl TW, Reynolds DS, "et al"
title=Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype
journal=Nat. Neurosci.
volume=3
issue=6
pages=587–92
year=2000
pmid=10816315
doi=10.1038/75761] 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.cite journal
author=Atack JR
title=The benzodiazepine binding site of GABA(A) receptors as a target for the development of novel anxiolytics
journal=Expert Opin Investig Drugs
volume=14
issue=5
pages=601–18
year=2005
pmid=15926867
doi=10.1517/13543784.14.5.601
url=http://www.expertopin.com/doi/abs/10.1517/13543784.14.5.601] cite journal
author=Morris HV, Dawson GR, Reynolds DS, Atack JR, Stephens DN
title=Both alpha2 and alpha3 GABAA receptor subtypes mediate the anxiolytic properties of benzodiazepine site ligands in the conditioned emotional response paradigm
journal=Eur. J. Neurosci.
volume=23
issue=9
pages=2495–504
year=2006
pmid=16706856
doi=10.1111/j.1460-9568.2006.04775.x
url=http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=0953-816X&date=2006&volume=23&issue=9&spage=2495] 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.cite journal
author=Mathiasen LS, Rodgers RJ, Mirza NR
title=Comparative effects of nonselective and subtype-selective gamma-aminobutyric acidA receptor positive modulators in the rat-conditioned emotional response test
journal=Behav Pharmacol
volume=18
issue=3
pages=191–203
year=2007
pmid=17426483
doi=10.1097/FBP.0b013e32814fcdd4
url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?an=00008877-200705000-00003] cite journal
author=Ujfalussy B, Kiss T, Orbán G, Hoffmann WE, Erdi P, Hajós M
title=Pharmacological and computational analysis of alpha-subunit preferential GABA(A) positive allosteric modulators on the rat septo-hippocampal activity
journal=Neuropharmacology
volume=52
issue=3
pages=733–43
year=2007
pmid=17113111
doi=10.1016/j.neuropharm.2006.09.022
url=http://linkinghub.elsevier.com/retrieve/pii/S0028-3908(06)00337-6]

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.cite journal
author=Mirza NR, Rodgers RJ, Mathiasen LS
title=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=J. Pharmacol. Exp. Ther.
volume=316
issue=3
pages=1291–9
year=2006
pmid=16339395
doi=10.1124/jpet.105.094003
url=http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=16339395] cite journal
author=Mathiasen L, Mirza NR
title=A comparison of chlordiazepoxide, bretazenil, L838,417 and zolpidem in a validated mouse Vogel conflict test
journal=Psychopharmacology (Berl.)
volume=182
issue=4
pages=475–84
year=2005
pmid=16133136
doi=10.1007/s00213-005-0119-z] The synthesis of L-838,417 and similar compounds was described in 2005 in the Journal of Medicinal Chemistrycite journal
author = Carling RW, Madin A, Guiblin A, "et al"
title = 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 = J. Med. Chem.
volume = 48
issue = 23
pages = 7089–92
year = 2005
pmid = 16279764
doi = 10.1021/jm058034a] .

References