Glaucine

Glaucine
Clinical data
AHFS/Drugs.comInternational Drug Names
ATC code
  • none
Identifiers
IUPAC name
  • (S)-5,6,6a,7-tetrahydro-1,2,9,10-tetramethoxy-6-methyl-4H-dibenzo[de,g]quinoline
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
CompTox Dashboard (EPA)
ECHA InfoCard100.006.820
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Chemical and physical data
FormulaC21H25NO4
Molar mass355.434 g·mol−1
3D model (JSmol)
SMILES
  • CN1CCc2cc(c(c-3c2[C@@H]1Cc4c3cc(c(c4)OC)OC)OC)OC
InChI
  • InChI=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 ☒N
  • Key:RUZIUYOSRDWYQF-HNNXBMFYSA-N ☒N
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Glaucine 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

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

Glaucine
(2 stereoisomers)

(S)-configuration
(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.[13] 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][14] 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.[15] Its enantiomers effect are same for adrenergic receptor yet different for 5-HT receptor. Both (R)-Glaucine and (S)-Glaucine antagonizes α1 receptor but (R)-Glaucine is partial agonist of 5-HT2 subtypes whereas (S)-Glaucine is positive allosteric modulator of 5-HT2.[16]

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]

Animal studies demonstrate the ability of glaucine to decrease heart rate and lower blood pressure,[17] 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.[18] 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.

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. ↑ 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. S2CID 44040818. 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. ↑ 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. ↑ Zetler, G. (1988). "Neuroleptic-like, anticonvulsant and antinociceptive effects of aporphine alkaloids: bulbocapnine, corytuberine, boldine and glaucine". Archives Internationales de Pharmacodynamie et de Thérapie. 296: 255–281. PMID 2907279.
  6. 1 2 3 4 5 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.
  7. ↑ 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.
  8. ↑ Remichkova M, Dimitrova P, Philipov S, Ivanovska N (October 2009). "Toll-like receptor-mediated anti-inflammatory action of glaucine and oxoglaucine" (PDF). Fitoterapia. 80 (7): 411–4. doi:10.1016/j.fitote.2009.05.016. PMID 19481591.
  9. ↑ Rovinskiĭ VI (September 1989). "[A case of hallucinogen-like action of glaucine]". Klinicheskaia Meditsina. 67 (9): 107–8. PMID 2586025.
  10. 1 2 3 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.
  11. 1 2 3 4 5 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. S2CID 21348503.
  12. 1 2 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. ↑ Nestler E, Hyman S & Malenka R. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). China: McGraw-Hill Companies.
  14. ↑ 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.
  15. ↑ Zhang Y, Wang Q, Liu R, Zhou H, Crommen J, Moaddel R, Jiang Z, Zhang T (May 2019). "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. doi:10.1016/j.chroma.2019.01.062. PMID 30712820.
  16. ↑ Heng HL, Chee CF, Thy CK, Tee JT, Chin SP, Herr DR, Buckle MJ, Paterson IC, Doughty SW, Abd Rahman N, Chung LY (February 2019). "In vitro functional evaluation of isolaureline, dicentrine and glaucine enantiomers at 5-HT2 and α1 receptors". Chemical Biology & Drug Design. 93 (2): 132–138. doi:10.1111/cbdd.13390. PMID 30216681.
  17. ↑ 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.
  18. ↑ 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.
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