Glaucine
Chemical compound
From Wikipedia, the free encyclopedia
Glaucine, also known as 1,2,9,10-tetramethoxyaporphine and sold under the brand names Glauvent and Tusidil among others, is an aporphine alkaloid, antitussive (cough suppressant), and hallucinogen.[1][2][3][4][5] It is found in several different plant species in the family Papaveraceae, such as Glaucium flavum,[6] Glaucium oxylobum, and Corydalis yanhusuo,[7][8] and in other plants such as Croton lechleri in the family Euphorbiaceae.[9] Glaucine was first described following isolation from Glaucium flavum in 1839 and its chemical structure became known in 1911.[1][10][11]
-Glaucine.svg)
(S)-Glaucine, the enantiomer mainly found in nature and used medically | |
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| Trade names | Glauvent, Tusidil, Tussiglaucin, Broncholytin, Broncholitin |
| Other names | (S)-Glaucine; 1,2,9,10-Tetramethoxyaporphine; Tetramethoxyaporphine; Boldine dimethyl ether |
| AHFS/Drugs.com | International Drug Names |
| Drug class | Antitussive (cough suppressant); Hallucinogen |
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| ECHA InfoCard | 100.006.820 |
| Chemical and physical data | |
| Formula | C21H25NO4 |
| Molar mass | 355.434 g·mol−1 |
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Uses
Medical
Glaucine is currently used as an antitussive agent in Iceland, as well as Romania, Bulgaria, Russia and other Eastern European countries.[1][12][5] Bulgarian pharmaceutical company Sopharma sells glaucine in tablet form, where a single dose contains 40 mg. It is known to be sold over-the-counter.[1]
Recreational
Reports of recreational use of glaucine have 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, and hallucinations.[13][5] Investigation of side effects in a clinical setting also reports that the hallucinatory effects manifest as bright and colorful visualizations. They further 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".[13]
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".[5]
Side effects
Glaucine may produce side effects such as sedation, sleepiness, fatigue, weakness, nausea, pupil dilation, and hallucinogenic effects such as visual hallucinations and dissociation.[1][14][13]
Pharmacology
Pharmacodynamics
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.[12] 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.[15] In this way, glaucine can prevent smooth muscle from contracting, allowing it to relax.
It is 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.[12]
Glaucine has been found to act on the serotonin 5-HT2 receptors.[16][17] (S)-Glaucine is partial agonist of the serotonin 5-HT2A and 5-HT2C receptors, whereas (R)-glaucine is a positive allosteric modulator of the serotonin 5-HT2A receptor and possibly of the other two serotonin 5-HT2 receptors.[16][17] At the serotonin 5-HT2A receptor, (S)-glaucine showed an affinity (Ki) of 966 nM, EC50 of 661 nM, and an Emax of 42%, whereas at the serotonin 5-HT2C receptor, it displayed an EC50 of 447 nM and an Emax of 52%.[16] Activation of the serotonin 5-HT2A receptor is notably known to be responsible for the hallucinogenic effects of serotonergic psychedelics like psilocybin, LSD, and mescaline.[18][19] However, while activation of the serotonin 5-HT2A receptor may be involved, the underlying mechanism of action responsible for the hallucinogenic effects of glaucine remains unknown.[1] Glaucine also shows affinity for the serotonin 5-HT1A and 5-HT7 receptors (Ki = 171 nM and 43 nM, respectively).[17]
Both (R)-glaucine and (S)-glaucine antagonize the α1-adrenergic receptor.[16] Glaucine has been demonstrated to be a dopamine receptor antagonist, favoring dopamine D1 and D1-like receptors.[5][20] Besides actions on monoamine receptors, glaucine inhibits monoamine oxidase A (MAO-A), but its IC50 could not be determined due to solubility issues.[21]
It has bronchodilator, neuroleptic,[22] and antiinflammatory effects, acting as a PDE4 inhibitor and calcium channel blocker,[12] TLRs plays role in its anti inflammatory effects.[23] Glaucine has been reported to reduce blood pressure and heart rate and to possess anticonvulsant and antinociceptive effects in animals.[24][25]
Pharmacokinetics
The pharmacokinetics of glaucine have been studied in humans[26] and in horses.[27] In addition, the in-vitro human metabolism of glaucine has been studied.[28]
Chemistry
Stereoisomerism
Glaucine is a racemic mixture of (S)- and (R)- enantiomers.[2] (S)-Glaucine is the form that mainly occurs in nature.[2] However, while it was originally believed that only (S)-glaucine occurs in nature, (R)-glaucine has since been found in fire poppy (Papaver californicum).[29] The form used in medicine appears to exclusively be the (S) enantiomer and not the racemic mixture or (R)- enantiomer.[2][4]
(RS)-Glaucine (racemic glaucine)
(S)-Glaucine (glaucine)
(R)-Glaucine
-Glaucine.svg)
Synthesis
The chemical synthesis of glaucine has been described.[2][1]
Analogues
Analogues of glaucine include other aporphine alkaloids like apomorphine, boldine, bulbocapnine, nantenine, nuciferine, and pukateine, among many others.[10][30][31]
Certain synthetic analogues of glaucine such as 2-hydroxy-11-(2-methylallyl)oxynoraporphine are known to act as highly potent and high-efficacy serotonin 5-HT2A and 5-HT2C receptor agonists.[32][33]
History
Glaucine was first described by J. M. Probst via isolation from Glaucium flavum (yellow horned poppy) in 1839.[10][11][34] However, its chemical identity was not elucidated until later by other researchers, such as Richard Fischer in 1901 (chemical formula) and J. Gadamer (chemical structure) in 1911.[1][10][35][36][37] The drug subsequently came to be used used medically as an antitussive (cough suppressant) in some Eastern European countries.[4][38] Glaucine was reported to produce hallucinogenic effects in 1989.[14][13] Later, it was reported as a novel designer recreational drug in 2008.[1][5] The drug was found to act as a serotonin 5-HT2A receptor partial agonist and positive allosteric modulator in 2019.[16]
Society and culture
Availability
Glaucine is marketed for use as an antitussive (cough suppressant) in Bulgaria, Croatia, and Romania.[4]
Research
Asthma
When ingested orally has been found to increase airway conductance in humans, and has been investigated as a treatment for asthma.[12][39] The bronchodilator activity of glaucine is thought to be related to its phosphodiesterase PDE4 inhibition.[12][39]