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Ariadne (drug)

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(Redirected from4C-D)
Psychoactive phenethylamine drug

Pharmaceutical compound
Ariadne
Clinical data
Trade namesDimoxamine (tentative)
Other namesARIADNE; 4-Methyl-2,5-dimethoxy-α-ethylphenethylamine; 2,5-Dimethoxy-4-methyl-α-ethylphenethylamine; 4C-D; 4C-DOM; "Four-carbon DOM"; α-Et-2C-D; α-Ethyl-2C-D; BL-3912; BL3912; Dimoxamine
Drug classSerotonin5-HT2A,5-HT2B, and5-HT2C receptoragonist; Non-hallucinogenicserotonin5-HT2A receptoragonist
Legal status
Legal status
  • ?
Identifiers
  • 1-(2,5-dimethoxy-4-methylphenyl)butan-2-amine
CAS Number
PubChemCID
ChemSpider
UNII
CompTox Dashboard(EPA)
Chemical and physical data
FormulaC13H21NO2
Molar mass223.316 g·mol−1
3D model (JSmol)
  • O(c1cc(c(OC)cc1C[C@H](N)CC)C)C
  • InChI=1S/C13H21NO2/c1-5-11(14)7-10-8-12(15-3)9(2)6-13(10)16-4/h6,8,11H,5,7,14H2,1-4H3 checkY
  • Key:MLYCFWZIAJAIGW-UHFFFAOYSA-N checkY
  (verify)

Ariadne, also known chemically as4C-D or4C-DOM, by its developmental code nameBL-3912, and by its former tentative brand nameDimoxamine, is a little-knownpsychoactive drug of thephenethylamine,amphetamine, andphenylisobutylamine families.[1][2][3][4] It is ahomologue of thepsychedelics2C-D andDOM.[1][2][3][4]

The drug is aserotonin receptoragonist, including of the serotonin5-HT2A receptor.[1] However, it is non-hallucinogenic in animals and humans, although it still has somepsychoactive effects.[1][2][3] It may be non-hallucinogenic due to lower-efficacypartial agonism of the serotonin 5-HT2A receptor.[1]

Ariadne was developed byAlexander Shulgin.[1][2] It was studied atBristol Laboratories as anantidepressant and for various other uses but was never marketed.[1][4][3] There has been renewed interest in Ariadne in the 2020s owing to increased interest in psychedelics for treatment ofpsychiatric disorders.[1]

Effects

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In his 1991 bookPiHKAL,Alexander Shulgin reported testing Ariadne on himself up to a dose of 32 mg, finding that it produced "the alert of a psychedelic, with none of the rest of the package".[2] Very little published data exists about the human pharmacology of Ariadne apart from Shulgin's limited testing; unpublished human trials reportedly observed somepsychoactive effects, but nohallucinations.[5][1]

In his 2011 bookThe Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds, Shulgin described (R)-Ariadne as increasingmental alertness and producing feelings ofwell-being at doses of 25 to 50 mg.[3] It was claimed to improve symptoms ofmanic depression inpsychotic individuals at doses of 50 to 100 mg and to improve symptoms ofParkinson's disease at a dosage of 100 mg/day.[3][1] Doses of up to 300 mg resulted in analtered state of consciousness but still no psychedelic effects.[1][3] For comparison, DOM shows psychoactive sub-hallucinogenic effects at doses of 1 to 3 mg and psychedelic effects at doses of more than 3 mg.[1]

Pharmacology

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Pharmacodynamics

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Ariadne is apotent andselectiveagonist of theserotonin5-HT2 receptors, including of the serotonin5-HT2A,5-HT2B, and5-HT2C receptors.[1] However, it is lessefficacious in activating the serotonin 5-HT2A receptor, including theGq, G11, andβ-arrestin2 signaling pathways, compared to the related drugDOM, and this weakerpartial agonism may be responsible for its lack of psychedelic effects.[1] In addition to the serotonin 5-HT2 receptors, Ariadne is a lower-affinity agonist of the serotonin5-HT1 receptors.[1] Ariadne shows essentially no activity at themonoamine transporters.[1]

Ariadne shows a markedly attenuatedhead-twitch response, a behavioral proxy of psychedelic effects, in animals.[1] It is thought that the reduced efficacy of Ariadne in activating the serotonin 5-HT2A receptor is responsible for its non-hallucinogenic nature.[1] Ariadne was also shown to produce stimulus generalization in rats trained to respond toMDMA[6] orLSD.[5] In monkeys, the drug was found to possiblyincrease motivation, as it caused monkeys that had stopped running mazes to begin running them again.[2] Ariadne has also been found to be effective in ananimal model ofParkinson's disease, where it reversedmotor deficits similarly tolevodopa.[1]

Serotonin 5-HT2A receptor agonists have been found to increasedopamine levels in thenucleus accumbens and othermesolimbic areas and non-hallucinogenic serotonin 5-HT2A receptor agonists like Ariadne may do so without producing psychedelic effects.[1] This action may underlie the preliminary observations of effectiveness of Ariadne in the treatment ofparkinsonism in animals and humans.[1]

Chemistry

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Ariadne, also known as 4-methyl-2,5-dimethoxy-α-ethylphenethylamine, is asubstituted phenethylamine andamphetaminederivative.[2][3] It is theanalogue of2,5-dimethoxy-4-methylamphetamine (DOM) in which theα-methylgroup has been replaced with an α-ethyl group and is the analogue of2,5-dimethoxy-4-methylphenethylamine (2C-D) with an ethyl group substituted at the α carbon.[1][2][3]

Ariadne's alternative name4C-DOM or4C-D stands for "four-carbon DOM", whereas the name of 2C-D stands for "two-carbon DOM".[1] Another name of Ariadne isα-Et-2C-D, which stands for α-ethyl-2C-D.[7]Racemic Ariadne is additionally known by the former developmental code nameBL-3912, while the (R)-enantiomer of Ariadne is known by the former developmental code nameBL-3912A.[1][3]

Other related compounds include4C-B (the α-ethyl homologue of2C-B andDOB) and4C-T-2 (the α-ethyl homologue of2C-T-2 andAleph-2).[2]

History

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Ariadne was first synthesized byAlexander Shulgin.[1][2] Shulgin reported that the drug was tested byBristol Laboratories as anantidepressant, in an anecdote where he was explaining how human testing is invaluable (compared to animal testing) on drugs that change the state of the mind. He said, "Before they launched into a full multi-clinic study to determine whether it's going to be worth the animal studies or not, every person on the board of directors took it."[4] InThe Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds (2011), he described it also being evaluated for increasingmental alertness ingeriatric individuals, treatingParkinson's disease, and treatingpsychosis andmanic depression.[3][1] The tentative commercial name of Ariadne wasDimoxamine.[3] (R)-Ariadne was said to have completedphase 2clinical trials, but the actual clinical data were never disclosed and further development was halted due to strategic economic reasons.[1]

See also

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References

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  1. ^abcdefghijklmnopqrstuvwxyzaaCunningham MJ, Bock HA, Serrano IC, Bechand B, Vidyadhara DJ, Bonniwell EM, et al. (January 2023)."Pharmacological Mechanism of the Non-hallucinogenic 5-HT2A Agonist Ariadne and Analogs".ACS Chemical Neuroscience.14 (1):119–135.doi:10.1021/acschemneuro.2c00597.PMC 10147382.PMID 36521179.
  2. ^abcdefghijAlexander T. Shulgin,Ann Shulgin (1991)."#8 ARIADNE; 4C-DOM; BL-3912; DIMOXAMINE; 1-(2,5- DIMETHOXY-4-METHYLPHENYL)-2-AMINOBUTANE; 2,5- DIMETHOXY-a-ETHYL-4-METHYLPHENETHYLAMINE".PiHKAL: A Chemical Love Story (1st ed.). Berkeley, CA: Transform Press. pp. 475–480.ISBN 978-0-9630096-0-9.OCLC 25627628.
  3. ^abcdefghijklShulgin A, Manning T, Daley PF (2011)."#7. ARIADNE".The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds. Vol. 1. Berkeley, CA: Transform Press. pp. 7–9.ISBN 978-0-9630096-3-0.OCLC 709667010.It was developed commercially by the Bristol-Myers Company to increase mental alertness in geriatric patients, and was patented in Germany, France, and the United States (Shulgin, 1974a, 1974b, 1977a). Its commercial name, Dimoxamine, does not have a classic female ring to it. [...] In normal human subjects, R-4C-DOM orally at 25—50 mg increased mental alertness and feelings of well-being. At 100 mg/day, the symptoms of Parkinson's disease went into remission. With psychotic patients there was a consistent relief of manic depression at doses of 50-100 mg (Shulgin, 1977a; Partyka et al., 1978). A single human oral ingestion of 270 mg produced a change of state of consciousness but evoked no psychedelic effects (Winter, 1980).
  4. ^abcdShulgin A (2021).The Nature of Drugs. Berkeley, California: Transform Press. pp. 299–300.ISBN 9780999547212.
  5. ^abWinter JC (1980-05-01). "Effects of the phenethylamine derivatives, BL-3912, fenfluramine, and Sch-12679, in rats trained with LSD as a discriminative stimulus".Psychopharmacology.68 (2):159–162.doi:10.1007/BF00432134.PMID 6776559.S2CID 12221170.
  6. ^Glennon RA (October 1993). "MDMA-like stimulus effects of alpha-ethyltryptamine and the alpha-ethyl homolog of DOM".Pharmacology, Biochemistry, and Behavior.46 (2):459–462.doi:10.1016/0091-3057(93)90379-8.PMID 7903460.S2CID 54356633.
  7. ^Halberstadt AL, Chatha M, Klein AK, Wallach J, Brandt SD (May 2020)."Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species".Neuropharmacology.167: 107933.doi:10.1016/j.neuropharm.2019.107933.PMC 9191653.PMID 31917152.

External links

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