{{Short description|Chemical compound}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Drugbox | Verifiedfields = changed | Watchedfields = changed | verifiedrevid = 447739670 | IUPAC_name = 6,7-Dimethoxy-3-(6-methyl-5,6,7,8-tetrahydro[1,3]dioxolo[4,5-''g'']isoquinolin-5-yl)-2-benzofuran-1(3''H'')-one | image = Hydrastine.svg | image_class = skin-invert-image | width = 200px
<!--Clinical data--> | tradename = | pregnancy_category = | legal_status = | routes_of_administration =
<!--Pharmacokinetic data--> | bioavailability = | metabolism = Hepatic | elimination_half-life = | excretion = Renal
<!--Identifiers--> | CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 118-08-1 | ATC_prefix = none | ATC_suffix = | ATC_supplemental = | PubChem = 197835 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = | ChEMBL_Ref = {{ebicite|changed|EBI}} | ChEMBL = 497942 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 171234 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 8890V3217X
<!--Chemical data--> | C=21 | H=21 | N=1 | O=6 | smiles = O=C2O[C@@H](c1ccc(OC)c(OC)c12)[C@@H]5N(C)CCc4c5cc3OCOc3c4 | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C21H21NO6/c1-22-7-6-11-8-15-16(27-10-26-15)9-13(11)18(22)19-12-4-5-14(24-2)20(25-3)17(12)21(23)28-19/h4-5,8-9,18-19H,6-7,10H2,1-3H3/t18-,19+/m1/s1 | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = JZUTXVTYJDCMDU-MOPGFXCFSA-N | melting_point = 132 }}
'''Hydrastine''' is an isoquinoline alkaloid which was discovered in 1851 by Alfred P. Durand.<ref>{{cite journal | vauthors = Perrins JD | title = On Hydrastine, an Alkaloid Occurring in Hydrastis Canadensis. | journal = Pharmaceutical Journal: A Weekly Record of Pharmacy and Allied Sciences | pages = 547– | date = July 1862 | url = https://books.google.com/books?id=IusKAAAAYAAJ&pg=PA547 | publisher = J. Churchill }}</ref> Nitric acid induced hydrolysis of hydrastine yields hydrastinine, which was patented by Bayer as a haemostatic drug in the early 1900s.<ref>{{citation|title=Römpp CD|publisher=Georg Thieme Verlag|year=2006}}</ref> It is present in ''Hydrastis canadensis'' (thus the name) and other plants of the family Ranunculaceae.
==Total synthesis==
The first attempt for the total synthesis of hydrastine was reported by Sir Robert Robinson and co-workers<ref name="Hope_1931">{{cite journal | vauthors = Hope E, Pyman FL, Remfry FG, Robinson R | title = XXXI.—A synthesis of hydrastine. Part I | journal = J. Chem. Soc. | pages = 236–247 | year = 1931 | doi = 10.1039/JR9310000236 | issn = 0368-1769 }}</ref> in 1931. Following studies<ref name="Haworth_1950">{{cite journal | vauthors = Haworth RD, Pinder AR, Robinson R | title = Synthesis of Hydrastine | journal = Nature | volume = 165 | issue = 4196 | pages = 529 | year = 1950 | doi = 10.1038/165529a0 | issn = 0028-0836 | bibcode = 1950Natur.165..529H | s2cid = 4198366 | doi-access = free }}</ref><ref name="Haworth_1950a">{{cite journal | vauthors = Haworth RD, Pinder AR | title = 360. A new route to the phthalide-isoquinoline bases, and a synthesis of (–)-hydrastine | journal = J. Chem. Soc. | pages = 1776–1780 | year = 1950 | doi = 10.1039/JR9500001776 | issn = 0368-1769 }}</ref> where the synthesis of the key lactonic amide intermediate (structure 4 in figure) was the most troublesome, the major breakthrough was achieved in 1981 when J. R. Falck and co-workers<ref name="Falck_1981">{{cite journal | vauthors = Falck JR, Manna S | title = An intramolecular passerini reaction: Synthesis of hydrastine. | journal = Tetrahedron Letters | volume = 22 | issue = 7 | pages = 619–620 | year = 1981 | doi = 10.1016/S0040-4039(01)92504-3 | author1-link = John R. Falck | issn = 0040-4039 }}</ref> reported a four-step total synthesis of hydrastine from simple starting materials. The key step in the Falck synthesis was using a Passerini reaction to construct the lactonic amide intermediate 4. :class=skin-invert-image|Falck’s total synthesis of hydrastine, the mechanism of the Passerini reaction for synthesis of the key intermediate is also illustrated Starting from a simple phenylbromide variant 1, alkylation reaction with lithium methylisocyanide gives the isocyanide intermediate 2. Reacting isocyanide intermediate 2 with opianic acid 3 initiated the intramolecular Passerini reaction to give the key lactonic amide intermediate 4. The tetrahydro-isoquinolin ring was formed by first a ring-closure reaction under dehydration conditions using POCl3 and then a catalyzed hydrogenation using PtO2 as the catalyst. Finally, hydrastine was synthesized by installing the N-methyl group via reductive amination reaction with formaldehyde.
== Biological action == Hydrastine acts as a convulsant in mice. It appears to do this by binding to bicuculline-sensitive GABA<sub>A</sub> receptors as a potent competitive antagonist. The action appears to be largely mediated by the (+) enantiomer (IC<sub>50</sub> of 0.4µM), as (-)-hydrastine is 180 times less potent in regards to this effect.<ref>{{cite journal | vauthors = Huang JH, Johnston GA | title = (+)-Hydrastine, a potent competitive antagonist at mammalian GABAA receptors | journal = British Journal of Pharmacology | volume = 99 | issue = 4 | pages = 727–730 | date = April 1990 | pmid = 2163278 | pmc = 1917537 | doi = 10.1111/j.1476-5381.1990.tb12997.x }}</ref>
== See also == * Bicuculline (very similar in structure)
== References == {{Reflist|2}}
== External links == * {{cite EB1911 | volume = 14 | pages = 34 | wstitle = Hydrastine }}
{{GABAergics}}
Category:Benzylisoquinoline alkaloids Category:GABAA receptor antagonists Category:Total synthesis Category:3-(5,6,7,8-tetrahydro-(1,3)dioxolo(4,5-g)isoquinolin-5-yl)-3H-2-benzofuran-1-ones Category:Methylenedioxyphenethylamines Category:Tetrahydroisoquinoline alkaloids