Chemistry:Glaucine

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Short description: Chemical compound
Glaucine
Glaucin V3.svg
Clinical data
AHFS/Drugs.comInternational Drug Names
ATC code
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Identifiers
CAS Number
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Chemical and physical data
FormulaC21H25NO4
Molar mass355.434 g·mol−1
3D model (JSmol)
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Glaucine (1,2,9,10-TetraMethoxyAporphine, Bromcholitin, Glauvent, Tusidil, Tussiglaucin) is an aporphine alkaloid found in several different plant species in the family Papaveraceae such as Glaucium flavum,[1] Glaucium oxylobum and Corydalis yanhusuo,[2][3] and in other plants like Croton lechleri in the family Euphorbiaceae.[4]

It has bronchodilator, neuroleptic[5] and antiinflammatory effects, acting as a PDE4 inhibitor and calcium channel blocker,[6] and is used medically as an antitussive in some countries.[7] TLRs plays role in its anti inflammatory effects.[8] Glaucine may produce side effects such as sedation, fatigue, and a hallucinogenic effect characterised by colourful visual images,[9][10] and has been detected as a novel psychoactive drug.[11] In a 2019 publication,[12] 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).[13]

Glaucine
(2 stereoisomers)
(S)-Glaucine
(S)-configuration
(R)-Glaucine
(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.[6] 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.[14] 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.[11][15] 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.[6]

Glaucine has also recently[12] 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.[16] Its enantiomers effect are same for adrenergic receptor yet different for 5-HT receptor. Both (R)-Glaucine and (S)-Glaucine antagonizes α1 receptor but (S)-Glaucine is partial agonist of 5-HT2 subtypes whereas (R)-Glaucine is positive allosteric modulator of 5-HT2.[17]

Uses

Medical

It is currently used as an antitussive agent in Iceland, as well as Romania, Bulgaria, Russia and other eastern European countries.[6][11] 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.[6]

Glaucine has been reported to reduce blood pressure, heart rate and possess anticonvulsant and antinoiciceptive effect in animals[18][19]

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.[10][11] 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".[10]

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".[11]

See also

References

  1. "HPLC Determination of Glaucine in Yellow Horn Poppy Grass (Glaucium flavum Crantz)". Pharmaceutical Chemistry Journal 38 (1): 441–442. August 2004. doi:10.1023/B:PHAC.0000048907.58847.c6. ISSN 0091-150X. "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". 
  2. "[Resource investigation and quality evaluation on wild Corydalis yanhusuo]". Zhongguo Zhong Yao Za Zhi = Zhongguo Zhongyao Zazhi = China Journal of Chinese Materia Medica 29 (5): 399–401. May 2004. PMID 15706885. 
  3. "Antifungal activity of the methanolic extract and alkaloids of Glaucium oxylobum". Fitoterapia 74 (5): 493–6. July 2003. doi:10.1016/s0367-326x(03)00113-8. PMID 12837370. 
  4. "Geographic distribution of three alkaloid chemotypes of Croton lechleri". Journal of Natural Products 65 (6): 814–9. June 2002. doi:10.1021/np000270v. PMID 12088421. 
  5. "Neuroleptic-like, anticonvulsant and antinociceptive effects of aporphine alkaloids: bulbocapnine, corytuberine, boldine and glaucine". Archives Internationales de Pharmacodynamie et de Therapie 296: 255–281. 1988. PMID 2907279. 
  6. 6.0 6.1 6.2 6.3 6.4 "Bronchodilator and anti-inflammatory activities of glaucine: In vitro studies in human airway smooth muscle and polymorphonuclear leukocytes". British Journal of Pharmacology 127 (7): 1641–51. August 1999. doi:10.1038/sj.bjp.0702702. PMID 10455321. 
  7. "Objective evaluation of dextromethorphan and glaucine as antitussive agents". British Journal of Clinical Pharmacology 17 (5): 521–4. May 1984. doi:10.1111/j.1365-2125.1984.tb02384.x. PMID 6375709. 
  8. "Toll-like receptor-mediated anti-inflammatory action of glaucine and oxoglaucine". Fitoterapia 80 (7): 411–4. October 2009. doi:10.1016/j.fitote.2009.05.016. PMID 19481591. https://hal-riip.archives-ouvertes.fr/pasteur-00736334/file/Fitoterapia_Ivanovska.pdf. 
  9. "[A case of hallucinogen-like action of glaucine]". Klinicheskaia Meditsina 67 (9): 107–8. September 1989. PMID 2586025. 
  10. 10.0 10.1 10.2 "[Acute glaucine syndrome in the physician's practice: the clinical picture and potential danger]". Klinicheskaia Meditsina 84 (11): 68–70. 2006. PMID 17243616. 
  11. 11.0 11.1 11.2 11.3 11.4 "Detection of the pharmaceutical agent glaucine as a recreational drug". European Journal of Clinical Pharmacology 64 (5): 553–4. May 2008. doi:10.1007/s00228-007-0451-9. PMID 18204834. 
  12. 12.0 12.1 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
  13. "A functionally conserved STORR gene fusion in Papaver species that diverged 16.8 million years ago". Nature Communications 13 (1): 3150. June 2022. doi:10.1038/s41467-022-30856-w. PMID 35672295. Bibcode2022NatCo..13.3150C. 
  14. Nestler E, Hyman S & Malenka R. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). China: McGraw-Hill Companies.
  15. "Structure-affinity relationships of halogenated predicentrine and glaucine derivatives at D1 and D2 dopaminergic receptors: halogenation and D1 receptor selectivity". Bioorganic & Medicinal Chemistry 13 (11): 3699–704. June 2005. doi:10.1016/j.bmc.2005.03.022. PMID 15862999. 
  16. "Rapid screening and identification of monoamine oxidase-A inhibitors from Corydalis Rhizome using enzyme-immobilized magnetic beads based method". Journal of Chromatography A 1592: 1–8. May 2019. doi:10.1016/j.chroma.2019.01.062. PMID 30712820. 
  17. "In vitro functional evaluation of isolaureline, dicentrine and glaucine enantiomers at 5-HT2 and α1 receptors". Chemical Biology & Drug Design 93 (2): 132–138. February 2019. doi:10.1111/cbdd.13390. PMID 30216681. 
  18. "Neuroleptic-like, anticonvulsant and antinociceptive effects of aporphine alkaloids: bulbocapnine, corytuberine, boldine and glaucine". Archives Internationales de Pharmacodynamie et de Therapie 296: 255–81. 1988. PMID 2907279. 
  19. "Study of the in vivo and in vitro cardiovascular effects of (+)-glaucine and N-carbethoxysecoglaucine in rats". British Journal of Pharmacology 114 (7): 1419–27. April 1995. doi:10.1111/j.1476-5381.1995.tb13364.x. PMID 7606346.