Idazoxan: Difference between revisions

{{Short description|Chemical compound}}

{{Infobox drug

| Verifiedfields = changed

| verifiedrevid = 404695247

| IUPAC_name = (±)-2-(2,3-dihydro-1,4-benzodioxin-2-yl)-4,5-dihydro-1''H''-imidazole

| image = Idazoxan-2D-skeletal.svg

| chirality = [[Racemic mixture]]

<!--Clinical data-->

| tradename =

| pregnancy_category =

| legal_status = Uncontrolled

<!--Pharmacokinetic data-->

| bioavailability =

| metabolism =

| elimination_half-life =

| excretion =

<!--Identifiers-->

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 79944-58-4

| ATC_prefix = none

| ATC_suffix =

| PubChem = 54459

| UNII_Ref = {{fdacite|changed|FDA}}

| UNII = Y310PA316B

| ChEMBL_Ref = {{ebicite|changed|EBI}}

| ChEMBL = 10316

| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}

| ChemSpiderID = 49184

| StdInChI_Ref = {{stdinchicite|changed|chemspider}}

| StdInChI = 1S/C11H12N2O2/c1-2-4-9-8(3-1)14-7-10(15-9)11-12-5-6-13-11/h1-4,10H,5-7H2,(H,12,13)

| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}

| StdInChIKey = HPMRFMKYPGXPEP-UHFFFAOYSA-N

<!--Chemical data-->

| C=11 | H=12 | N=2 | O=2

| smiles = C1CN=C(N1)C2COC3=CC=CC=C3O2

'''Idazoxan''' ([[International Nonproprietary Name|INN]]) is a [[drug]] which is used in [[scientific research]]. It acts as both a selective [[alpha-2 receptor|α₂]] [[adrenergic receptor]] [[Receptor antagonist|antagonist]], and an antagonist for the [[imidazoline receptor]].<ref>{{cite journal | vauthors = Bousquet P, Bruban V, Schann S, Greney H, Ehrhardt JD, Dontenwill M, Feldman J | title = Participation of imidazoline receptors and alpha(2-)-adrenoceptors in the central hypotensive effects of imidazoline-like drugs | journal = Annals of the New York Academy of Sciences | volume = 881 | issue = 1 | pages = 272–8 | date = June 1999 | pmid = 10415925 | doi = 10.1111/j.1749-6632.1999.tb09369.x | bibcode = 1999NYASA.881..272B | s2cid = 38772290 }}</ref><ref>{{cite journal | vauthors = Clarke RW, Harris J | title = RX 821002 as a tool for physiological investigation of alpha(2)-adrenoceptors | journal = CNS Drug Reviews | volume = 8 | issue = 2 | pages = 177–92 | year = 2002 | pmid = 12177687 | pmc = 6741674 | doi = 10.1111/j.1527-3458.2002.tb00222.x }}</ref><ref>{{cite journal | vauthors = Yakubu MA, Hamilton CA, Howie CA, Reid JL | title = Idazoxan and brain alpha2-adrenoceptor in the rabbit | journal = Brain Research | volume = 436 | pages = 289–296 | date = 1988 | PMID = 2848612 | doi = 10.1016/0006-8993(88)90402-7 }}</ref><ref>{{cite journal | vauthors = Hamilton CA, Yakubu MA, Jardine E, Reid JL | title = Imidazole binding sites in rabbit kidney and forebrain membranes | journal = J Auton Pharmacol | volume = 11 | issue = 4 | pages = 277–83 | date = 1991 | PMID = 1939285 | doi = 10.1111/j.1474-8673.1991.tb00325.x }}</ref> Idazoxan has been under investigation as an [[antidepressant]], but it did not reach the market as such. More recently, it is under investigation as an adjunctive treatment in [[schizophrenia]]. Due to its α₂ receptor antagonism it is capable of enhancing therapeutic effects of [[antipsychotics]], possibly by enhancing [[dopamine]] [[neurotransmission]] in the [[prefrontal cortex]] of the brain, a brain area thought to be involved in the [[pathogenesis]] of schizophrenia.

== Alzheimer's research ==

Mice treated with idazoxan, which blocks the [[Alpha-2A adrenergic receptor|α_2A receptor]] which regulates [[norepinephrine]], behaved similarly to control animals despite still having amyloid-beta plaques in the brain, as a proof-of-concept experiment that dramatically reduced [[Alzheimer's disease|Alzheimer's]] pathology and symptoms in two mouse models, potentially offering an immediate treatment for this devastating disease.<ref name="pmid31941827">{{cite journal | vauthors = Zhang F, Gannon M, Chen Y, Yan S, Zhang S, Feng W, Tao J, Sha B, Liu Z, Saito T, Saido T, Keene CD, Jiao K, Roberson ED, Xu H, Wang Q | display-authors = 6 | title = β-amyloid redirects norepinephrine signaling to activate the pathogenic GSK3β/tau cascade | journal = Science Translational Medicine | volume = 12 | issue = 526 | date = January 2020 | pmid = 31941827 | pmc = 7891768 | doi = 10.1126/scitranslmed.aay6931 }}</ref>

==Synthesis==

Note that the literature method claims that the old original patented procedure gives a different reaction product formed through a rearrangement.

[[File:Idazoxan synthesis.svg|thumb|501px|center|Synthesis:<ref>{{cite journal | vauthors = Chapleo CB, Myers PL | title = 2-[2-(1, 4-benzodioxanyl)]-2-imidazoline hydrochloride. | journal = Tetrahedron Letters | date = January 1981 | volume = 22 | issue = 48 | pages = 4839–4842 | doi = 10.1016/S0040-4039(01)92358-5 }}</ref><ref>{{cite journal | vauthors = Chapleo CB, Davis JA, Myers PL, Readhead MJ, Stillings MR, Welbourn AP, Hampson FC, Sugden K | title = An investigation of some base induced transformations of the 1, 4‐benzodioxan ring system. | journal = Journal of Heterocyclic Chemistry | date = January 1984 | volume = 21 | issue = 1 | pages = 77–80 | doi = 10.1002/jhet.5570210117 | doi-access = free }}</ref><ref name="Chapleo_1983">{{cite journal | vauthors = Chapleo CB, Myers PL, Butler RC, Doxey JC, Roach AG, Smith CF | title = alpha-adrenoreceptor reagents. 1. Synthesis of some 1,4-benzodioxans as selective presynaptic alpha 2-adrenoreceptor antagonists and potential antidepressants | journal = Journal of Medicinal Chemistry | volume = 26 | issue = 6 | pages = 823–31 | date = June 1983 | pmid = 6133953 | doi = 10.1021/jm00360a008 }}</ref> Old Patent:<ref>{{cite patent | country = US | number = 2979511 | title = Certain 1, 4-benzodioxanyl imidazolines and corresponding pyrimidines and process | inventor = Krapcho J, Lott WA | assign1 = Olin Corp | gdate = 11 April 1961 | postscript = . }}</ref> New Patent:<ref>{{cite patent | country = US | number = 7338970 | title = Pharmaceutical composition based on idazoxan, salts, hydrates or polymorphs thereof | inventor = Bougaret J, Avan JL, Segonds R | gdate = 3 March 2008 | assign1 = Pierre Fabre Medicament | postscript = . }}</ref>]]

The reaction of catechol ('''1''') with 2-Chloroacrylonitrile [920-37-6] ('''2''') gives 2-cyano-1,4-benzodioxan [1008-92-0] ('''3'''). [[Pinner reaction]] with alcoholic hydrogen chloride leads to the iminoether,<ref>{{cite web | url = https://pubchem.ncbi.nlm.nih.gov/compound/10035919 | title = 2,3-Dihydro-1,4-benzodioxin-2-carbimidic acid ethyl ester | work = PubChem | publisher = U.S. National Library of Medicine |id = CID:10035919 }}</ref> ('''4'''). Treatment with [[ethylenediamine]] [107-15-3] ('''5''') gives the imidazoline ring affording ''{{Highlight|Idazoxin}}'' ('''6''').

*[[Imiloxan]]

{{Reflist|2}}

{{Imidazolinergics}}

[[Category:Imidazoline antagonists]]

[[Category:Benzodioxans]]

{{nervous-system-drug-stub}}