Etifoxine

Etifoxine

Systematic (IUPAC) name
6-Chloro-N-ethyl-4-methyl-4-phenyl-4H-benzo[d][1,3]oxazin-2-amine
Clinical data
AHFS/Drugs.com	International Drug Names
Pregnancy category	Not recommended. Crosses the placental barrier
Routes of administration	Oral
Legal status
Legal status	US: Not FDA approved; unscheduled
Pharmacokinetic data
Bioavailability	90%
Metabolism	Hepatic (no CYP450 interactions)[1]
Biological half-life	2 to 6 hours (etifoxine), 20 to 30 hours (active metabolite)[2]
Excretion	Renal[1]
Identifiers
CAS Number	21715-46-8
ATC code	N05BX03 (WHO)
PubChem	CID 30768
IUPHAR/BPS	5468
DrugBank	DB08986
ChemSpider	28547
UNII	X24X82MX4X
KEGG	D07320
ChEMBL	CHEMBL2106227
Chemical data
Formula	C17H17ClN2O
Molar mass	300.782 g/mol
SMILES ClC1=CC=C2N=C(NCC)OC(C3=CC=CC=C3)(C)C2=C1
InChI InChI=1S/C17H17ClN2O/c1-3-19-16-20-15-10-9-13(18)11-14(15)17(2,21-16)12-7-5-4-6-8-12/h4-11H,3H2,1-2H3,(H,19,20) Key:IBYCYJFUEJQSMK-UHFFFAOYSA-N
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Etifoxine (INN,^[3] also known as etafenoxine; trade name Stresam) is an anxiolytic and anticonvulsant drug^[4][5] developed by Hoechst in the 1960s.^[3] It is used in some countries for anxiety disorders.^[6] It has similar effects to benzodiazepine drugs, but is structurally distinct and does not bind to the benzodiazepine receptor.^[7] It is more effective than lorazepam as an anxiolytic, and has fewer side effects.^[8] Etifoxine is not approved by the U.S. Food and Drug Administration or the European Medicines Agency.

Side effects

Etifoxine has been associated with acute liver injury.^[1]

Mechanism of action

Unlike benzodiazepines, etifoxine appears to produce its anxiolytic effects by binding to β2 and β3 subunits of the GABA_A receptor complex, and so is acting at a different target site to benzodiazepines, although the physiological effect that is produced is similar to that of benzodiazepines.^[9] This difference in binding means that etifoxine can be used alongside benzodiazepines to potentiate their effects without competing for binding sites;^[10] however, it also means that the effects of etifoxine are not reversed by the benzodiazepine antagonist flumazenil.^[11]

References

1. Mennecier D, Rimlinger H, Gidenne S; et al. (November 2003). "[Etifoxine chlorhydrate-induced acute hepatitis]". Gastroenterol. Clin. Biol. (in French) 27 (11): 1050–1. PMID 14732859.
2. "Stresam PI" (PDF). Adcock Ingram. n.d. Retrieved 2008-08-30.
3. U.S. Patent 3,725,404
4. Kruse HJ, Kuch H (1985). "Etifoxine: evaluation of its anticonvulsant profile in mice in comparison with sodium valproate, phenytoin and clobazam". Arzneimittelforschung 35 (1): 133–135.
5. The Merck Index, 12th Edition. 3910.
6. Girard C, Liu S, Cadepond F, Adams D, Lacroix C, Verleye M, Gillardin JM, Baulieu EE, Schumacher M, Schweizer-Groyer G (2008). "Etifoxine improves peripheral nerve regeneration and functional recovery". Proc Natl Acad Sci U S A 105 (51): 20505–10. doi:10.1073/pnas.0811201106.
7. Schlichter R, Rybalchenko V, Poisbeau P, Verleye M, Gillardin J (2000). "Modulation of GABAergic synaptic transmission by the non-benzodiazepine anxiolytic etifoxine". Neuropharmacology 39 (9): 1523–35.
8. Nguyen N, Fakra E, Pradel V, Jouve E, Alquier C, Le Guern ME, Micallef J, Blin O (2006). "Efficacy of etifoxine compared to lorazepam monotherapy in the treatment of patients with adjustment disorders with anxiety: a double-blind controlled study in general practice". Human Psychopharmacology 21 (3): 139–49.
9. Hamon A, Morel A, Hue B, Verleye M, Gillardin JM (2003). "The modulatory effects of the anxiolytic etifoxine on GABA(A) receptors are mediated by the beta subunit". Neuropharmacology 45 (3): 293–303.
10. Kruse HJ, Kuch H (1986). "Potentiation of clobazam's anticonvulsant activity by etifoxine, a non-benzodiazepine tranquilizer, in mice. Comparison studies with sodium valproate". Arzneimittelforschung 36 (9): 1320–2.
11. Verleye M, Schlichter R, Gillardin JM (1999). "Interactions of etifoxine with the chloride channel coupled to the GABA(A) receptor complex". Neuroreport 10 (15): 3207–10.