Ariadne (drug)

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Ariadne
Ariadne.svg
Clinical data
Trade names Dimoxamine (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 class Serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptor agonist; Non-hallucinogenic serotonin 5-HT2A receptor agonist
Legal status
Legal status
  •  ?
Identifiers
  • 1-(2,5-dimethoxy-4-methylphenyl)butan-2-amine
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
Formula C13H21NO2
Molar mass 223.316 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 Yes check.svgY
  • Key:MLYCFWZIAJAIGW-UHFFFAOYSA-N Yes check.svgY
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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]

Contents

The drug is a serotonin receptor agonist, including of the serotonin 5-HT2A 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-HT2A 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 [2] Very little published data exists about the human pharmacology of Ariadne apart from Shulgin's limited testing; unpublished human trials reportedly observed some psychoactive effects, but no hallucinations.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-HT2A, 5-HT2B, and 5-HT2C receptors. [1] However, it is less efficacious in activating the serotonin 5-HT2A receptor, including the Gq, 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-HT2A 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-HT2A receptor agonists have been found to increase dopamine levels in the nucleus accumbens and other mesolimbic 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 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]

See also

Related Research Articles

<span class="mw-page-title-main">2C-B</span> Psychoactive drug

2C-B (4-bromo-2,5-dimethoxyphenethylamine), also known as Nexus, is a synthetic psychedelic drug of the 2C family, mainly used as a recreational drug. It was first synthesized by Alexander Shulgin in 1974 for use in psychotherapy. To date, there is limited scientific information regarding the drug's pharmacokinetics and pharmacological effects in humans. The existing studies primarily classify 2C-B as a stimulant and hallucinogen, and less commonly an entactogen and empathogen.

<span class="mw-page-title-main">2,5-Dimethoxy-4-methylamphetamine</span> Chemical compound

2,5-Dimethoxy-4-methylamphetamine is a psychedelic and a substituted amphetamine. It was first synthesized by Alexander Shulgin, and later reported in his book PiHKAL: A Chemical Love Story. DOM is classified as a Schedule I substance in the United States, and is similarly controlled in other parts of the world. Internationally, it is a Schedule I drug under the Convention on Psychotropic Substances. It is generally taken orally.

<span class="mw-page-title-main">2,5-Dimethoxy-4-bromoamphetamine</span> Chemical compound

Dimethoxybromoamphetamine (DOB), also known as brolamfetamine and bromo-DMA, is a psychedelic drug and substituted amphetamine of the phenethylamine class of compounds. DOB was first synthesized by Alexander Shulgin in 1967. Its synthesis and effects are documented in Shulgin's book PiHKAL: A Chemical Love Story.

<span class="mw-page-title-main">2C-T-8</span> Chemical compound

2C-T-8 is a psychedelic phenethylamine of the 2C family. It was first synthesized by Alexander Shulgin, sometimes used as an entheogen.

<span class="mw-page-title-main">2C-T-4</span> Chemical compound

2C-T-4 (2,5-dimethoxy-4-isopropylthiophenethylamine) is a psychedelic phenethylamine of the 2C family. It was first synthesized by Alexander Shulgin and is used as entheogenic recreational drug.

<span class="mw-page-title-main">MBDB</span> Chemical compound

MBDB, also known as N-methyl-1,3-benzodioxolylbutanamine or as 3,4-methylenedioxy-N-methyl-α-ethylphenylethylamine, is an entactogen of the phenethylamine, amphetamine, and phenylisobutylamine families related to MDMA. It is known by the street names "Eden" and "Methyl-J".

<span class="mw-page-title-main">2C-T</span> Chemical compound

2C-T is a psychedelic and hallucinogenic drug of the 2C family. It is used by some as an entheogen. It has structural and pharmacodynamic properties similar to the drugs mescaline and 2C-T-2.

<span class="mw-page-title-main">2C-TFM</span> Psychedelic phenethylamine drug

2C-TFM is a psychedelic phenethylamine of the 2C family. It was first synthesized in the laboratory of David E. Nichols. It has also been called 2C-CF3, a name derived from the Para-trifluoromethyl group it contains.

<span class="mw-page-title-main">2,5-Dimethoxy-4-ethylamphetamine</span> Psychedelic drug

2,5-Dimethoxy-4-ethylamphetamine is a psychedelic drug of the phenethylamine and amphetamine chemical classes. It was first synthesized by Alexander Shulgin, and was described in his book PiHKAL.

<span class="mw-page-title-main">2C (psychedelics)</span> Family of phenethylamine psychedelics

2C (2C-x) is a general name for the family of psychedelic phenethylamines containing methoxy groups on the 2 and 5 positions of a benzene ring. Most of these compounds also carry lipophilic substituents at the 4 position, usually resulting in more potent and more metabolically stable and longer acting compounds. Most of the currently known 2C compounds were first synthesized by Alexander Shulgin in the 1970s and 1980s and published in his book PiHKAL. Shulgin also coined the term 2C, being an acronym for the 2 carbon atoms between the benzene ring and the amino group.

<span class="mw-page-title-main">Aleph (psychedelic)</span> Chemical compound

Aleph is a psychedelic hallucinogenic drug and a substituted amphetamine of the phenethylamine class of compounds, which can be used as an entheogen. It was first synthesized by Alexander Shulgin, who named it after the first letter of the Hebrew alphabet. In his book PiHKAL, Shulgin lists the dosage range as 5–10 mg, with effects typically lasting for 6 to 8 hours.

<span class="mw-page-title-main">2C-T-13</span> Chemical compound

2C-T-13 is a psychedelic phenethylamine of the 2C family. It was presumably first synthesized by Alexander Shulgin and reported in his book PiHKAL.

<span class="mw-page-title-main">2C-T-15</span> Chemical compound

2C-T-15 or 2,5-dimethoxy-4-(β-cyclopropylthio)phenethylamine is a psychedelic phenethylamine of the 2C family. It was presumably first synthesized by Alexander Shulgin and reported in his book PiHKAL .

<span class="mw-page-title-main">2C-T-17</span> Chemical compound

2C-T-17 or 2,5-dimethoxy-4-(β-secbutylthio)phenethylamine is a psychedelic phenethylamine of the 2C family. It was presumably first synthesized by Alexander Shulgin and reported in his book PiHKAL .

<span class="mw-page-title-main">2,5-Dimethoxy-4-butylamphetamine</span> Substituted amphetamine psychedelic drug

2,5-Dimethoxy-4-butylamphetamine (DOBU) is a lesser-known psychedelic drug and a substituted amphetamine. DOBU was first synthesized by Alexander Shulgin. In his book PiHKAL (Phenethylamines i Have Known And Loved), only low dosages of 2–3 mg were tested, with the duration simply listed as "very long". DOBU produces paresthesia and difficulty sleeping, but with few other effects. Compared to shorter chain homologues such as DOM, DOET and DOPR which are all potent hallucinogens, DOBU has an even stronger 5-HT2 binding affinity but fails to substitute for hallucinogens in animals or produce hallucinogenic effects in humans, suggesting it has low efficacy and is thus an antagonist or weak partial agonist at the 5-HT2A receptor.

<span class="mw-page-title-main">2,5-Dimethoxy-4-amylamphetamine</span> Chemical compound

Dimethoxy-4-amylamphetamine (DOAM) is a lesser-known psychedelic drug and a substituted amphetamine. DOAM was first synthesized by Alexander Shulgin. In his book PiHKAL (Phenethylamines i Have Known And Loved), the minimum dosage is listed as 10 mg, and the duration is unknown. DOAM produces a bare threshold and tenseness. As the 4-alkyl chain length is increased from shorter homologues such as DOM, DOET and DOPR which are all potent hallucinogens, the 5-HT2 binding affinity increases, rising to a maximum with the 4-(n-hexyl) derivative before falling again with even longer chains, but compounds with chain length longer than n-propyl, or with other bulky groups such as isopropyl, t-butyl or γ-phenylpropyl at the 4- position, fail to substitute for hallucinogens in animals or produce hallucinogenic effects in humans, suggesting these have low efficacy and are thus antagonists or partial agonists at the 5-HT2A receptor.

<span class="mw-page-title-main">2,5-Dimethoxy-4-ethoxyamphetamine</span> Psychedelic drug

2,5-Dimethoxy-4-ethoxyamphetamine (MEM) is a psychedelic drug of the phenethylamine and amphetamine chemical classes. It was first synthesized by Alexander Shulgin. In his book PiHKAL, he lists the active dose range as 20–50 mg, and the duration as 10–14 hours. According to Shulgin, MEM produces color enhancement, visual phenomena, and pattern movement, among other effects.

<span class="mw-page-title-main">Phenylisobutylamine</span> Stimulant drug of the phenethylamine class

Phenylisobutylamine, also known as α-ethylphenethylamine, Butanphenamine, B or AEPEA, is a stimulant drug of the phenethylamine class. It is a higher homologue of amphetamine, differing from amphetamine's molecular structure only by the substitution of the methyl group at the alpha position of the side chain with an ethyl group.

<span class="mw-page-title-main">2,5-Dimethoxy-4-fluoroamphetamine</span> Chemical compound

2,5-Dimethoxy-4-fluoroamphetamine (DOF) is a psychedelic drug of the phenethylamine and amphetamine classes. Alexander Shulgin briefly describes DOF in his book PiHKAL:

Animal studies that have compared DOF to the highly potent DOI and DOB imply that the human activity will be some four to six times less than these two heavier halide analogues.

<span class="mw-page-title-main">4C-B</span> Chemical compound

4C-B is a lesser-known psychedelic drug which is related to 2C-B and DOB. It is a reasonably potent 5-HT2A receptor partial agonist with a Ki of 7.6nM, but has relatively low efficacy. It is briefly mentioned in Alexander Shulgin's book PiHKAL but was never tested by him, however it has subsequently been tested by other researchers and was found to be active in a dose range of 50-80mg with a duration of around 8 hours, though with generally milder effects than 2C-B or DOB.

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 Cunningham 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. 1 2 3 4 5 6 7 8 9 10 Shulgin AT, Shulgin A (1991). PiHKAL: A Chemical Love Story (1st ed.). Berkeley, CA: Transform Press. ISBN   9780963009609. OCLC   25627628.
  3. 1 2 3 4 5 6 7 8 9 10 11 12 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).
  4. 1 2 3 4 Shulgin A (2021). The Nature of Drugs. Berkeley, California: Transform Press. pp. 299–300. ISBN   9780999547212.
  5. 1 2 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.
  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.
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