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Ariadne
Clinical data
Trade names	Dimoxamine (tentative)
Other names	ARIADNE; 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 class	Serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptor agonist; Non-hallucinogenic serotonin 5-HT2A receptor agonist
Legal status
Legal status	?;
Identifiers
	IUPAC name 1-(2,5-dimethoxy-4-methylphenyl)butan-2-amine;
CAS Number	52842-58-7 ; 52842-59-8 ((R)-isomer);
PubChem CID	169886;
ChemSpider	148565 ;
UNII	09426ZTO78;
CompTox Dashboard (EPA)	DTXSID501343240 DTXSID30967314, DTXSID501343240 ;
Chemical and physical data
Formula	C13H21NO2
Molar mass	223.316 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES O(c1cc(c(OC)cc1C[C@H](N)CC)C)C;
	InChI 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 ; Key:MLYCFWZIAJAIGW-UHFFFAOYSA-N ;
	(verify)

Ariadne, also known chemically as 4C-D or 4C-DOM, by its developmental code name BL-3912, and by its former tentative brand name Dimoxamine, is a little-known psychoactive drug of the phenethylamine, amphetamine, and phenylisobutylamine families.^[1]^[2]^[3]^[4] It is a homologue of the psychedelics 2C-D and DOM.^[1]^[2]^[3]^[4]

The drug is a serotonin receptor agonist, including of the serotonin 5-HT_2A receptor.^[1] However, it is non-hallucinogenic in animals and humans, although it still has some psychoactive effects.^[1]^[2]^[3] It may be non-hallucinogenic due to lower-efficacy partial agonism of the serotonin 5-HT_2A receptor.^[1]

Ariadne was developed by Alexander Shulgin.^[1]^[2] It was studied at Bristol Laboratories as an antidepressant 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 of psychiatric disorders.^[1]

Effects

In his 1991 book PiHKAL, 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Very little published data exists about the human pharmacology of Ariadne apart from Shulgin's limited testing; unpublished human trials reportedly observed some psychoactive effects, but no hallucinations.^[5]^[1]

In his 2011 book The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds, Shulgin described (R)-Ariadne as increasing mental alertness and producing feelings of well-being at doses of 25 to 50 mg.^[3] It was claimed to improve symptoms of manic depression in psychotic individuals at doses of 50 to 100 mg and to improve symptoms of Parkinson's disease at a dosage of 100 mg/day.^[3]^[1] Doses of up to 300 mg resulted in an altered 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

Pharmacodynamics

Ariadne is a potent and selective agonist of the serotonin 5-HT₂ receptors, including of the serotonin 5-HT_2A, 5-HT_2B, and 5-HT_2C receptors.^[1] However, it is less efficacious in activating the serotonin 5-HT_2A receptor, including the G_q, G₁₁, and β-arrestin2 signaling pathways, compared to the related drug DOM, and this weaker partial 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 serotonin 5-HT₁ receptors.^[1] Ariadne shows essentially no activity at the monoamine transporters.^[1]

Ariadne shows a markedly attenuated head-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-HT_2A receptor is responsible for its non-hallucinogenic nature.^[1] Ariadne was also shown to produce stimulus generalization in rats trained to respond to MDMA^[6] or LSD.^[5] In monkeys, the drug was found to possibly increase 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 an animal model of Parkinson's disease, where it reversed motor deficits similarly to levodopa.^[1]

Serotonin 5-HT_2A receptor agonists have been found to increase dopamine levels in the nucleus accumbens and other mesolimbic areas and non-hallucinogenic serotonin 5-HT_2A 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 of parkinsonism in animals and humans.^[1]

Chemistry

Ariadne, also known as 4-methyl-2,5-dimethoxy-α-ethylphenethylamine, is a substituted phenethylamine and amphetamine derivative.^[2]^[3] It is the analogue of 2,5-dimethoxy-4-methylamphetamine (DOM) in which the α-methyl group has been replaced with an α-ethyl group and is the analogue of 2,5-dimethoxy-4-methylphenethylamine (2C-D) with an ethyl group substituted at the α carbon.^[1]^[2]^[3]

Ariadne's alternative name 4C-DOM or 4C-D stands for "four-carbon DOM", whereas the name of 2C-D stands for "two-carbon DOM".^[1] Another name of Ariadne is α-Et-2C-D, which stands for α-ethyl-2C-D.^[7] Racemic Ariadne is additionally known by the former developmental code name BL-3912, while the (R)-enantiomer of Ariadne is known by the former developmental code name BL-3912A.^[1]^[3]

Other related compounds include 4C-B (the α-ethyl homologue of 2C-B and DOB) and 4C-T-2 (the α-ethyl homologue of 2C-T-2 and Aleph-2).^[2]

History

Ariadne was first synthesized by Alexander Shulgin.^[1]^[2] Shulgin reported that the drug was tested by Bristol Laboratories as an antidepressant, 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] In The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds (2011), he described it also being evaluated for increasing mental alertness in geriatric individuals, treating Parkinson's disease, and treating psychosis and manic depression.^[3]^[1] The tentative commercial name of Ariadne was Dimoxamine.^[3] (R)-Ariadne was said to have completed phase 2 clinical trials, but the actual clinical data were never disclosed and further development was halted due to strategic economic reasons.^[1]

References

^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q ^r ^s ^t ^u ^v ^w ^x ^y ^z ^aa Cunningham MJ, Bock HA, Serrano IC, Bechand B, Vidyadhara DJ, Bonniwell EM, et al. (January 2023). "Pharmacological Mechanism of the Non-hallucinogenic 5-HT_2A Agonist Ariadne and Analogs". ACS Chemical Neuroscience. 14 (1): 119–135. doi:10.1021/acschemneuro.2c00597. PMC 10147382. PMID 36521179.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j Shulgin AT, Shulgin A (1991). PiHKAL: A Chemical Love Story (1st ed.). Berkeley, CA: Transform Press. ISBN 9780963009609. OCLC 25627628.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l Shulgin A, Manning T, Daley PF (2011). The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds. Vol. 1. Berkeley: Transform Press. pp. 7–9. ISBN 978-0-9630096-3-0. 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).
^ ^a ^b ^c ^d Shulgin A (2021). The Nature of Drugs. Berkeley, California: Transform Press. pp. 299–300. ISBN 9780999547212.
^ ^a ^b Winter 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.
^ 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.
^ 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.