glaucine

{{Drugbox

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| IUPAC_name = (S)-5,6,6a,7-tetrahydro-1,2,9,10-tetramethoxy-6-methyl-4H-dibenzo[de,g]quinoline

| image = Glaucine.svg

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| CAS_number = 475-81-0

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{{CAS|5630-11-5}}

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| StdInChI = 1S/C21H25NO4/c1-22-7-6-12-9-18(25-4)21(26-5)20-14-11-17(24-3)16(23-2)10-13(14)8-15(22)19(12)20/h9-11,15H,6-8H2,1-5H3/t15-/m0/s1

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| C=21 | H=25 | N=1 | O=4

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Glaucine (also known as 1,2,9,10-tetramethoxyaporphine, bromcholitin, glauvent, tusidil, and tussiglaucin) is an aporphine alkaloid found in several different plant species in the family Papaveraceae, such as Glaucium flavum,{{cite journal | vauthors = Lapa GB, Sheichenko OP, Serezhechkin AG, Tolkachev ON |date=August 2004 |title=HPLC Determination of Glaucine in Yellow Horn Poppy Grass (Glaucium flavum Crantz) |journal=Pharmaceutical Chemistry Journal |volume=38 |issue=1 |pages=441–442 |issn=0091-150X |doi=10.1023/B:PHAC.0000048907.58847.c6 |s2cid=44040818 |quote=S-(+)-Glaucine (C₂₁H₂₅NO₄) is the main alkaloid component in the grass of yellow horn poppy (Glaucium luteum L., syn. Glaucium flavum Crantz) of the family Papaveraceae}} Glaucium oxylobum, and Corydalis yanhusuo,{{cite journal | vauthors = Xu XH, Yu GD, Wang ZT | title = [Resource investigation and quality evaluation on wild Corydalis yanhusuo] | journal = Zhongguo Zhong Yao Za Zhi = Zhongguo Zhongyao Zazhi = China Journal of Chinese Materia Medica | volume = 29 | issue = 5 | pages = 399–401 | date = May 2004 | pmid = 15706885 }}{{cite journal | vauthors = Morteza-Semnani K, Amin G, Shidfar MR, Hadizadeh H, Shafiee A | title = Antifungal activity of the methanolic extract and alkaloids of Glaucium oxylobum | journal = Fitoterapia | volume = 74 | issue = 5 | pages = 493–6 | date = July 2003 | pmid = 12837370 | doi = 10.1016/s0367-326x(03)00113-8 }} and in other plants such as Croton lechleri in the family Euphorbiaceae.{{cite journal | vauthors = Milanowski DJ, Winter RE, Elvin-Lewis MP, Lewis WH | title = Geographic distribution of three alkaloid chemotypes of Croton lechleri | journal = Journal of Natural Products | volume = 65 | issue = 6 | pages = 814–9 | date = June 2002 | pmid = 12088421 | doi = 10.1021/np000270v }}

It has bronchodilator, neuroleptic{{cite journal | vauthors = Zetler G | title = Neuroleptic-like, anticonvulsant and antinociceptive effects of aporphine alkaloids: bulbocapnine, corytuberine, boldine and glaucine | journal = Archives Internationales de Pharmacodynamie et de Therapie | volume = 296 | pages = 255–281 | year = 1988 | pmid = 2907279 }} and antiinflammatory effects, acting as a PDE4 inhibitor and calcium channel blocker,{{cite journal | vauthors = Cortijo J, Villagrasa V, Pons R, Berto L, Martí-Cabrera M, Martinez-Losa M, Domenech T, Beleta J, Morcillo EJ | display-authors = 6 | title = Bronchodilator and anti-inflammatory activities of glaucine: In vitro studies in human airway smooth muscle and polymorphonuclear leukocytes | journal = British Journal of Pharmacology | volume = 127 | issue = 7 | pages = 1641–51 | date = August 1999 | pmid = 10455321 | pmc = 1566148 | doi = 10.1038/sj.bjp.0702702 }} and is used medically as an antitussive in some countries.{{cite journal | vauthors = Rühle KH, Criscuolo D, Dieterich HA, Köhler D, Riedel G | title = Objective evaluation of dextromethorphan and glaucine as antitussive agents | journal = British Journal of Clinical Pharmacology | volume = 17 | issue = 5 | pages = 521–4 | date = May 1984 | pmid = 6375709 | pmc = 1463443 | doi = 10.1111/j.1365-2125.1984.tb02384.x }} TLRs plays role in its anti inflammatory effects.{{cite journal |vauthors=Remichkova M, Dimitrova P, Philipov S, Ivanovska N |title=Toll-like receptor-mediated anti-inflammatory action of glaucine and oxoglaucine |journal=Fitoterapia |volume=80 |issue=7 |pages=411–4 |date=October 2009 |pmid=19481591 |doi=10.1016/j.fitote.2009.05.016 |url= https://hal-riip.archives-ouvertes.fr/pasteur-00736334/file/Fitoterapia_Ivanovska.pdf|issn=}} Glaucine may produce side effects such as sedation, fatigue, and a hallucinogenic effect characterised by colourful visual images,{{cite journal | vauthors = Rovinskiĭ VI | title = [A case of hallucinogen-like action of glaucine] | journal = Klinicheskaia Meditsina | volume = 67 | issue = 9 | pages = 107–8 | date = September 1989 | pmid = 2586025 }}{{cite journal | vauthors = Rovinskiĭ VI | title = [Acute glaucine syndrome in the physician's practice: the clinical picture and potential danger] | journal = Klinicheskaia Meditsina | volume = 84 | issue = 11 | pages = 68–70 | year = 2006 | pmid = 17243616 }} and has been detected as a novel psychoactive drug.{{cite journal | vauthors = Dargan PI, Button J, Hawkins L, Archer JR, Ovaska H, Lidder S, Ramsey J, Holt DW, Wood DM | display-authors = 6 | title = Detection of the pharmaceutical agent glaucine as a recreational drug | journal = European Journal of Clinical Pharmacology | volume = 64 | issue = 5 | pages = 553–4 | date = May 2008 | pmid = 18204834 | doi = 10.1007/s00228-007-0451-9 | s2cid = 21348503 }} In a 2019 publication,Heng, HL, Chee, CF, Thy, CK, et al. In vitro functional evaluation of isolaureline, dicentrine and glaucine enantiomers at 5‐HT2 and α1 receptors. Chem Biol Drug Des. 2019; 93: 132– 138. https://doi.org/10.1111/cbdd.13390 the isomer (R)-glaucine is reported to be a positive allosteric modulator of the 5-HT2A receptor, which is also associated with the hallucinogenic effects of substances such as psilocybin and mescaline.

Chemistry

=Stereoisomerism=

It was believed that only the (S)-form of glaucine occurs in nature until (R)-glaucine was found in fire poppy (Papaver californicum).{{cite journal | vauthors = Catania T, Li Y, Winzer T, Harvey D, Meade F, Caridi A, Leech A, Larson TR, Ning Z, Chang J, Van de Peer Y, Graham IA | display-authors = 6 | title = A functionally conserved STORR gene fusion in Papaver species that diverged 16.8 million years ago | journal = Nature Communications | volume = 13 | issue = 1 | pages = 3150 | date = June 2022 | pmid = 35672295 | pmc = 9174169 | doi = 10.1038/s41467-022-30856-w | bibcode = 2022NatCo..13.3150C }}

class="wikitable" style="text-align:center"

class="hintergrundfarbe6"

! colspan="2"| Glaucine
(2 stereoisomers)

File:(S)-Glaucin V2.svg
(S)-configuration

| File:(R)-Glaucin V2.svg
(R)-configuration

Mechanism of action

Glaucine binds to the benzothiazepine site on L-type Ca²⁺-channels, thereby blocking calcium ion channels in smooth muscle like the human bronchus. Glaucine has no effect on intracellular calcium stores, but rather, does not allow the entry of Ca²⁺ after intracellular stores have been depleted. Ca²⁺ influx is a vital component in the process of muscular contraction, and the blocking of this influx therefore reduces the ability of the muscle to contract.Nestler E, Hyman S & Malenka R. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). China: McGraw-Hill Companies. In this way, glaucine can prevent smooth muscle from contracting, allowing it to relax.

Glaucine has also been demonstrated to be a dopamine receptor antagonist, favoring D1 and D1-like receptors.{{cite journal | vauthors = Asencio M, Hurtado-Guzmán C, López JJ, Cassels BK, Protais P, Chagraoui A | title = Structure-affinity relationships of halogenated predicentrine and glaucine derivatives at D1 and D2 dopaminergic receptors: halogenation and D1 receptor selectivity | journal = Bioorganic & Medicinal Chemistry | volume = 13 | issue = 11 | pages = 3699–704 | date = June 2005 | pmid = 15862999 | doi = 10.1016/j.bmc.2005.03.022 }} It is also a non-competitive selective inhibitor of PDE4 in human bronchial tissue and granulocytes. PDE4 is an isoenzyme that hydrolyzes cyclic AMP to regulate human bronchial tone (along with PDE3). Yet as a PDE4 inhibitor, glaucine possesses very low potency.

Glaucine has also recently been found to have an effect on the neuronal 5-HT2A receptors, which are responsible for the hallucinogenic effects of classical psychedelics. It also inhibits MAO enzymes.{{cite journal |vauthors=Zhang Y, Wang Q, Liu R, Zhou H, Crommen J, Moaddel R, Jiang Z, Zhang T |title=Rapid screening and identification of monoamine oxidase-A inhibitors from Corydalis Rhizome using enzyme-immobilized magnetic beads based method |journal=Journal of Chromatography A |volume=1592 |issue= |pages=1–8 |date=May 2019 |pmid=30712820 |doi=10.1016/j.chroma.2019.01.062 |s2cid=73448412 |url= |issn=}} Its enantiomers effect are same for adrenergic receptor yet different for 5-HT receptor. Both (R)-glaucine and (S)-glaucine antagonize α1 receptor, but (S)-glaucine is partial agonist of 5-HT₂ subtypes whereas (R)-glaucine is a positive allosteric modulator of 5-HT₂.{{cite journal |vauthors=Heng HL, Chee CF, Thy CK, Tee JT, Chin SP, Herr DR, Buckle MJ, Paterson IC, Doughty SW, Abd Rahman N, Chung LY |title=In vitro functional evaluation of isolaureline, dicentrine and glaucine enantiomers at 5-HT2 and α1 receptors |journal=Chemical Biology & Drug Design |volume=93 |issue=2 |pages=132–138 |date=February 2019 |pmid=30216681 |doi=10.1111/cbdd.13390 |s2cid=52278437 |url= |issn=}}

Uses

= Medical =

It is currently used as an antitussive agent in Iceland, as well as Romania, Bulgaria, Russia and other eastern European countries. Bulgarian pharmaceutical company Sopharma sells glaucine in tablet form, where a single dose contains 40 mg and the half-life is indicated to be 6–8 hours. When ingested orally has been shown to increase airway conductance in humans, and has been investigated as a treatment for asthma.

Glaucine has been reported to reduce blood pressure, heart rate and possess anticonvulsant and antinoiciceptive effect in animals.{{cite journal | vauthors = Zetler G | title = Neuroleptic-like, anticonvulsant and antinociceptive effects of aporphine alkaloids: bulbocapnine, corytuberine, boldine and glaucine | journal = Archives Internationales de Pharmacodynamie et de Therapie | volume = 296 | pages = 255–81 | year = 1988 | pmid = 2907279 }}{{cite journal | vauthors = Orallo F, Fernández Alzueta A, Campos-Toimil M, Calleja JM | title = Study of the in vivo and in vitro cardiovascular effects of (+)-glaucine and N-carbethoxysecoglaucine in rats | journal = British Journal of Pharmacology | volume = 114 | issue = 7 | pages = 1419–27 | date = April 1995 | pmid = 7606346 | pmc = 1510273 | doi = 10.1111/j.1476-5381.1995.tb13364.x }}

= Recreational =

Reports of recreational use of glaucine have recently been published, and effects include dissociative-type symptoms; feeling detached and 'in another world', as well as nausea, vomiting and dilated pupils. These reports mirror those about the effects of clinical use, which state dissociative-type symptoms as well as lethargy, fatigue, hallucinations. Investigation of side effects in a clinical setting also reports that the hallucinatory effects manifest as bright and colorful visualizations. They also report that patients perceive their environments clearly yet feel detached from it; "the patient sees and understands everything and is oriented well enough, but cannot take a clear and adequate action".

One particular report of recreational use gone awry described the form of distribution as tablets being marketed as a 1-benzylpiperazine (BZP)-free "herbal high" which the patient referred to as "head candy".