Glaucine

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Glaucine
Glaucin V3.svg
Clinical data
AHFS/Drugs.comInternational Drug Names
ATC code
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Identifiers
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ECHA InfoCard100.006.820 Edit this at Wikidata
Chemical and physical data
FormulaC21H25NO4
Molar mass355.428 g/mol g·mol−1
3D model (JSmol)
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Glaucine is an 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 and antiinflammatory effects, acting as a PDE4 inhibitor and calcium channel blocker,[5] and is used medically as an antitussive in some countries.[6] Glaucine may produce side effects such as sedation, fatigue, and a hallucinogenic effect characterised by colourful visual images,[7][8] and has been detected as a novel psychoactive drug.[9] In a 2019 publication,[10] 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.

Stereoisomerism[edit]

The (S)-form of glaucine occurs in nature, but the (R)-form does not.

Glaucine
(2 stereoisomers)
(S)-Glaucine
(S)-configuration
(R)-Glaucine
(R)-configuration

Mechanism of action[edit]

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.[5] 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.[11] 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.[9][12] 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.[5]

Glaucine has also recently[10] been found to have an effect on the neuronal 5-HT2A receptors, which are responsible for the hallucinogenic effects of classical psychedelics.

Clinical use[edit]

It is currently used as an antitussive agent in Iceland, as well as Romania, Bulgaria, Russia and other eastern European countries.[5][9] 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.[5]

Animal studies demonstrate the ability of glaucine to decrease heart rate and lower blood pressure,[13] presumably by the same mechanism of Ca2+-channel antagonism that it uses to relax bronchial muscle. Studies of the effect of several alkaloids in mice, including glaucine, demonstrate anticonvulsant and antinociceptive properties.[14] In other words; animal studies indicate that glaucine can also act as a pain reliever to a certain extent, although its capacities in this respect appear limited when compared to other analgesics.

Symptoms and recreational use[edit]

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.[8][9] 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”.[8]

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”.[9]

See also[edit]

References[edit]

  1. ^ Lapa GB, Sheichenko OP, Serezhechkin AG, Tolkachev ON (August 2004). "HPLC Determination of Glaucine in Yellow Horn Poppy Grass (Glaucium flavum Crantz)". Pharmaceutical Chemistry Journal. 38 (1): 441–442. 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 Papaveraceae family
  2. ^ Xu XH, Yu GD, Wang ZT (May 2004). "[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. PMID 15706885.
  3. ^ Morteza-Semnani K, Amin G, Shidfar MR, Hadizadeh H, Shafiee A (July 2003). "Antifungal activity of the methanolic extract and alkaloids of Glaucium oxylobum". Fitoterapia. 74 (5): 493–6. doi:10.1016/s0367-326x(03)00113-8. PMID 12837370.
  4. ^ Milanowski DJ, Winter RE, Elvin-Lewis MP, Lewis WH (June 2002). "Geographic distribution of three alkaloid chemotypes of Croton lechleri". Journal of Natural Products. 65 (6): 814–9. doi:10.1021/np000270v. PMID 12088421.
  5. ^ a b c d e Cortijo J, Villagrasa V, Pons R, Berto L, Martí-Cabrera M, Martinez-Losa M, et al. (August 1999). "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. doi:10.1038/sj.bjp.0702702. PMC 1566148. PMID 10455321.
  6. ^ Rühle KH, Criscuolo D, Dieterich HA, Köhler D, Riedel G (May 1984). "Objective evaluation of dextromethorphan and glaucine as antitussive agents". British Journal of Clinical Pharmacology. 17 (5): 521–4. doi:10.1111/j.1365-2125.1984.tb02384.x. PMC 1463443. PMID 6375709.
  7. ^ Rovinskiĭ VI (September 1989). "[A case of hallucinogen-like action of glaucine]". Klinicheskaia Meditsina. 67 (9): 107–8. PMID 2586025.
  8. ^ a b c Rovinskiĭ VI (2006). "[Acute glaucine syndrome in the physician's practice: the clinical picture and potential danger]". Klinicheskaia Meditsina. 84 (11): 68–70. PMID 17243616.
  9. ^ a b c d e Dargan PI, Button J, Hawkins L, Archer JR, Ovaska H, Lidder S, et al. (May 2008). "Detection of the pharmaceutical agent glaucine as a recreational drug". European Journal of Clinical Pharmacology. 64 (5): 553–4. doi:10.1007/s00228-007-0451-9. PMID 18204834.
  10. ^ a b 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
  11. ^ Nestler E, Hyman S & Malenka R. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). China: McGraw-Hill Companies.
  12. ^ Asencio M, Hurtado-Guzmán C, López JJ, Cassels BK, Protais P, Chagraoui A (June 2005). "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. doi:10.1016/j.bmc.2005.03.022. PMID 15862999.
  13. ^ Orallo F, Fernández Alzueta A, Campos-Toimil M, Calleja JM (April 1995). "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. doi:10.1111/j.1476-5381.1995.tb13364.x. PMC 1510273. PMID 7606346.
  14. ^ Zetler G (1988). "Neuroleptic-like, anticonvulsant and antinociceptive effects of aporphine alkaloids: bulbocapnine, corytuberine, boldine and glaucine". Archives Internationales de Pharmacodynamie et de Therapie. 296: 255–81. PMID 2907279.