2,5-Dimethoxy-4-propylamphetamine

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DOPR
2,5-Dimethoxy-4-propylamphetamine.svg
DOPR-3d-sticks.png
Clinical data
Other names2,5-Dimethoxy-4-propylamphetamine
Legal status
Legal status
Identifiers
  • 1-(2,5-Dimethoxy-4-propylphenyl)propan-2-amine
CAS Number
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ChEMBL
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Chemical and physical data
Formula C14H23NO2
Molar mass 237.343 g·mol−1
3D model (JSmol)
  • O(c1cc(c(OC)cc1CC(N)C)CCC)C
  • InChI=1S/C15H25NO2/c1-5-6-11-8-14(17-4)12(7-10(2)15)9-13(11)16-3/h8-10H,5-7,15H2,1-4H3 X mark.svgN
  • Key:UEEAUFJYLUJWQJ-UHFFFAOYSA-N Yes check.svgY
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2,5-Dimethoxy-4-propylamphetamine (DOPR) 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 (Phenethylamines i Have Known And Loved). Shulgin described DOPR as a "heavy duty psychedelic", complete with alterations of the thought process and visual distortion. [1] Very little data exists about the pharmacological properties, metabolism, and toxicity of DOPR.

Contents

Pharmacology

Pharmacodynamics

DOPR acts as an agonist of the serotonin 5-HT2 receptors, including of the serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors. [2] [3] [4] It produces the head-twitch response (HTR), a behavioral proxy of psychedelic effects, in rodents. [4] As with many other psychedelics, DOPR shows an inverted U-shaped dose–response curve in terms of the HTR, increasing it at lower doses and having diminished effectiveness at higher doses. [4] DOPR showed no significant effects on locomotor activity in rodents at the assessed doses, but showed a trend towards hyperlocomotion at the highest dose. [4] The drug has shown pro-motivational effects in rodents at sub-hallucinogenic doses or so-called "microdoses". [2] [3] DOPR's close analogue 2,5-dimethoxy-4-ethylamphetamine (DOET) has also been clinically studied at sub-hallucinogenic doses as a "psychic energizer". [5] [6] [7] [8] [9] [10] The non-hallucinogenic analogue Ariadne has indirect dopaminergic effects in rodents [4] and pro-motivational effects in monkeys as well. [11]

Chemistry

Analogues

The alternative structural isomer DOIP, with a 4-isopropyl substitution, is also known but is around ten times weaker than DOPR, with an active dose of some 20–30 mg (as compared to 2–5 mg for DOPR). [1]

Structure of DOIP DOIP structure.png
Structure of DOIP

See also

References

  1. 1 2 Shulgin A, Shulgin A (September 1991). PiHKAL: A Chemical Love Story. United States: Transform Press. p. 978. ISBN   0-9630096-0-5.
  2. 1 2 Noback M, Kenton JA, Klein AK, Hughes ZA, Kruegel AC, Schmid Y, Halberstadt AL, Young JW (February 2025). "Low (micro)doses of 2,5-dimethoxy-4-propylamphetamine (DOPR) increase effortful motivation in low-performing mice". Neuropharmacology. 268: 110334. doi:10.1016/j.neuropharm.2025.110334. PMID   39900138. According to a recent publication (Cunningham et al., 2023), DOPR acts as a potent agonist at the 5-HT2A receptor when tested in BRET assays of Gq dissociation (EC50 = 1.7 nM, Emax = 98.9% relative to 5-HT) and β-arrestin2 recruitment (EC50 = 7.96 nM, Emax = 99.8% relative to 5-HT).
  3. 1 2 Noback M, Kenton J, Klein A, Hughes Z, Kruegel A, Young J (December 2022). "ACNP 61st Annual Meeting: Poster Abstracts P541 - P809: P572. 2,5-Dimethoxy-4-Propylamphetamine (DOPR) Increased Effortful Motivation in Mice". Neuropsychopharmacology. 47 (Suppl 1): 371–520 (390–390). doi:10.1038/s41386-022-01486-z. PMC   9714408 . PMID   36456695. DOPR caused a dose-dependent increase in HTR (F(5,30)=60.0, p < 0.0001), with doses of 3.2 and 10 mg/kg passing a Bonferroni post hoc correction relative to vehicle (p < 0.002), and peak effect at 3.2 mg/kg. [...] The binding affinity at 5-HT2A of the two compounds was similar, with DOPR having a Ki of 17.56 nM and DOI having a Ki of 14.51 nM. [...] DOPR and DOI also show agonist activity at 5-HT2A (EC50 of 0.12 and 0.19 nM, respectively) and 5-HT2C (EC50 of 0.27 and 0.82 nM, respectively) receptors, with >25-fold lower potency at 5-HT2B receptors and no significant activity at 5-HT1A (both > 1,000 nM EC50). [...] The positive effect of DOPR on effortful motivation points to possible therapeutic applications in psychiatric illness states characterized by reduced effortful motivation as measured by the PRBT. The similarity of effects of DOPR to well-studied drugs such as DOI and amphetamine provides a useful reference point to interpret its pharmacological effects. Importantly, the doses needed to increase breakpoint in the PRBT were as low as 0.0106 mg/kg. While 0.1 mg/kg increased HTR, this effect was not significant, and maximal effect at 3.2 mg/kg, supporting the premise that low doses of DOPR may be therapeutic in anhedonia states without causing unwanted hallucinogenic side effects.
  4. 1 2 3 4 5 Cunningham MJ, Bock HA, Serrano IC, Bechand B, Vidyadhara DJ, Bonniwell EM, Lankri D, Duggan P, Nazarova AL, Cao AB, Calkins MM, Khirsariya P, Hwu C, Katritch V, Chandra SS, McCorvy JD, Sames D (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. We propose the following rationale for the rapid effects of Ariadne in the mouse [Parkinson's disease (PD)] model, as an initial guiding hypothesis for future studies. The in vitro profile suggests that Ariadne's effect on dopamine neurotransmission is indirect, namely not via direct modulation of DAT or dopamine receptors. It has been demonstrated that 5-HT2A agonists increase dopamine release in nucleus accumbens and other regions of the mesolimbic system.43 It is therefore likely that 5-HT2A agonists also stimulate DA release in more dorsal areas of the striatum that are compromised by the PD pathology.
  5. ↑ Baggott MJ (1 October 2023). "Learning about STP: A Forgotten Psychedelic from the Summer of Love" (PDF). History of Pharmacy and Pharmaceuticals. 65 (1): 93–116. doi: 10.3368/hopp.65.1.93 . ISSN   2694-3034 . Retrieved 26 January 2025.
  6. ↑ Shulgin AT (1978). "Psychotomimetic Drugs: Structure-Activity Relationships". In Iversen LL, Iversen SD, Snyder SH (eds.). Stimulants. Boston, MA: Springer US. pp. 243–333. doi:10.1007/978-1-4757-0510-2_6. ISBN   978-1-4757-0512-6.
  7. ↑ Snyder SH, Faillace LA, Weingartner H (September 1968). "DOM (STP), a new hallucinogenic drug, and DOET: effects in normal subjects". Am J Psychiatry. 125 (3): 113–120. doi:10.1176/ajp.125.3.357. PMID   4385937.
  8. ↑ Snyder SH, Faillace LA, Weingartner H (July 1969). "A new psychotropic agent. Psychological and physiological effects of 2,5-dimethoxy-4-ethyl amphetamine (DOET) in man". Arch Gen Psychiatry. 21 (1): 95–101. doi:10.1001/archpsyc.1969.01740190097014. PMID   4389442.
  9. ↑ Snyder SH, Weingartner H, Faillace LA (January 1971). "DOET (2,5-dimethoxy-4-ethylamphetamine), a new psychotropic drug. Effects of varying doses in man". Arch Gen Psychiatry. 24 (1): 50–55. doi:10.1001/archpsyc.1971.01750070052006. PMID   4923215.
  10. ↑ Snyder SH, Unger S, Blatchley R, Barfknecht CF (July 1974). "Stereospecific actions of DOET (2,5-dimethoxy-4-ethylamphetamine) in man". Arch Gen Psychiatry. 31 (1): 103–106. doi:10.1001/archpsyc.1974.01760130079013. PMID   4599412.
  11. ↑ Alexander 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. His company did many animal tests, one of which showed that it was not hallucinogenic (a cat whose tail erected dramatically with DOM did nothing with ARIADNE) and another that showed re-motivation (some old maze-running monkeys who had decided not to run any more mazes changed their minds with ARIADNE).
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