2C-iBu

Last updated
2C-iBu
2C-iBu.svg
Clinical data
Other names2,5-Dimethoxy-4-isobutylphenethylamine; 4-Isobutyl-2,5-dimethoxyphenethylamine; 2C-iBu; 2C-IB; ELE-02; ELE02; ELEU02
Routes of
administration 		Oral; [1] Ophthalmic [2] [3]
Drug class Serotonin 5-HT2A receptor agonist; Serotonergic psychedelic; Hallucinogen; Anti-inflammatory drug
Pharmacokinetic data
Protein binding 74% [4]
Duration of action 20 hours [1]
Identifiers
  • 2-[2,5-dimethoxy-4-(2-methylpropyl)phenyl]ethanamine
PubChem CID
Chemical and physical data
Formula C14H23NO2
Molar mass 237.343 g·mol−1
3D model (JSmol)
  • CC(C)CC1=C(C=C(C(=C1)OC)CCN)OC
  • InChI=1S/C14H23NO2/c1-10(2)7-12-9-13(16-3)11(5-6-15)8-14(12)17-4/h8-10H,5-7,15H2,1-4H3
  • Key:FLBABUVVTQBINW-UHFFFAOYSA-N

2,5-Dimethoxy-4-isobutylphenethylamine (2C-iBu or 2C-IB), also known by its developmental code name ELE-02, is a serotonin 5-HT2A receptor agonist, serotonergic psychedelic, and anti-inflammatory drug which is under development for the treatment of inflammation. [2] [3] [4] [5] [6] [7] It is a member of the phenethylamine and 2C families of compounds. [4] [5] [7] The drug is being developed as a topical eye drop for treatment of inflammatory eye conditions. [2] [3] There is also interest in 2C-iBu and related drugs for treatment of systemic inflammation and neuroinflammation. [8] [9] [10] [11] [12] [5]

Contents

2C-iBu was not assessed or discovered by Alexander Shulgin and was not described in PiHKAL (Phenethylamines I Have Known and Loved) (1991). [7] [13] However, he did include 2C-iBu (as "2C-IB") as a DOM analogue in a table in The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds (2011). [1] In addition, he stated in a footnote that a 5 mg oral dose of 2C-iBu produces threshold activity and has a long duration of about 20 hours. [1] The cited source for these observations was a 2006 personal communication with "M. Mueller". [1]

2C-iBu was subsequently more thoroughly characterized by Charles D. Nichols and colleagues at Eleusis as a novel anti-inflammatory drug in the late 2010s. [4] [7] The drug has reached the preclinical research stage of development, but no recent development has been reported as of October 2023. [2] [3]

Pharmacology

2C-iBu molecular targets [4]
Target Affinity (pKi)
2C-iBu (R)-DOI
5-HT1A 7.15.9
5-HT1B 7.35.6
5-HT1D 7.2ND
5-HT2A 8.910.4
5-HT2B 7.88.6
5-HT2C 9.69.2
5-HT6 5.9ND
5-HT7 6.5ND

2C-iBu is a highly potent and robustly efficacious serotonin 5-HT2A receptor agonist. [4] Its EC50 Tooltip half-maximal effective concentration values are 1.3 nM for calcium mobilization and 57.5 nM for β-arrestin-2 recruitment, whereas its Emax Tooltip maximal efficacy values are 103% for calcium mobilization and 77% for β-arrestin-2 recruitment relative to serotonin. [4] The drug showed higher potency and efficacy as a serotonin 5-HT2A receptor agonist than several other 2C drugs, including 2C-NP, 2C-B, 2C-I, 2C-H, and 2C-iP, whereas its activities were more comparable to or less than those of the DOx drugs DOIB, (R)-DOB, (R)-DOI, and DOiP. [4] 2C-iBu has also been assessed and found to bind to other serotonin receptors, including the serotonin 5-HT2C, 5-HT2B, 5-HT1B, 5-HT1D, 5-HT1A, 5-HT7, and 5-HT6 receptors, in that order of affinity and with varying avidities. [4]

2C-iBu dose-dependently produces the head-twitch response (HTR), a behavioral proxy of psychedelic effects, in rodents. [4] In terms of ED50 Tooltip median effective dose, 2C-iBu is about 3-fold less potent than (R)-DOI in producing the HTR. [4] According to Eleusis, it is expected to have "greatly reduced" psychoactivity or hallucinogenic effects compared to related drugs like other members of the 2C family. [6] [14]

The drug is effective in an allergic asthma model in rodents and showed similar potency as (R)-DOI. [4] Due to its reduced potency in producing the HTR but retained anti-inflammatory potency, 2C-iBu is expected to show greater separation between the desired anti-inflammatory and the undesired psychedelic effects in humans compared to (R)-DOI. [4] In contrast to certain other anti-inflammatory drugs like corticosteroids, serotonin 5-HT2A receptor agonists like 2C-iBu are not immunosuppressants. [14]

Chemistry

2C-iBu, also known as 2,5-dimethoxy-4-isobutylphenethylamine, is a phenethylamine and 2C derivative. [4] [5] [7]

Related drugs to 2C-iBu include the tert-butyl (2C-tBU) and cyclopropyl methyl (2C-CPM) analogues. [4] In addition, 2C-iBu is related to DOx drugs such as DOIB (DOiBu). [4] [15] According to Charles D. Nichols, 2,5-dimethoxyamphetamine (2,5-DMA) has potent anti-inflammatory activity with weak or no hallucinogenic effects. [7] [15] Moreover, DOTFM has potent psychedelic effects with no anti-inflammatory activity. [7] [16] [17] Hence, it appears that the anti-inflammatory effects and psychedelic effects of serotonin 5-HT2A receptor agonists can be fully dissociated. [7]

The chemical synthesis of 2C-iBu has been described. [4] [1]

Clinical development

2C-iBu was developed as a novel anti-inflammatory drug by Charles D. Nichols and colleagues at Eleusis in the late 2010s. [7] [4] They are developing it for treatment of inflammatory conditions. [2] [3] Eleusis was acquired by and merged into Beckley Psytech in October 2022. [2] [18] [19] The drug has reached the preclinical research stage of development, but no recent development has been reported as of October 2023. [2] [3] Eleusis has patent protection for 2C-iBu. [6] [4]

2C-iBu is not a controlled substance in the United States as of 2020. [6]

See also

References

  1. 1 2 3 4 5 6 Shulgin A, Manning T, Daley PF (2011). "#60. DOM". The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds . Vol. 1. Berkeley, CA: Transform Press. pp. 118–129. ISBN   978-0-9630096-3-0. OCLC   709667010. 2c-IB: [...] (15) Synthesis (from 2,5-dimethoxyisobutylbenzene) (Mueller, 2006); although this compound was reported here, a structure-search in Chemical Abstracts does not produce a CAS registry number (16) Threshold activity in humans at 5 mg orally; long duration (about 20 hours; Mueller, 2006). [...] Mueller, M. (2006) Personal communication with A.T. Shulgin.
  2. 1 2 3 4 5 6 7 "ELE 02". AdisInsight. 28 October 2023. Retrieved 16 February 2025.
  3. 1 2 3 4 5 6 "Delving into the Latest Updates on ELE-02 with Synapse". Synapse. 23 January 2025. Retrieved 16 February 2025.
  4. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 WOpublished 2020210823, Charles D. Nichols; Gerald Billac& David E. Nichols,"Compounds and methods for treating inflammatory disorders",published 15 October 2020
  5. 1 2 3 4 Shlomi Raz, Eleusis (February 2020). Eleusis Drug Development Overview. LSX World Congress 2020.
  6. 1 2 3 4 Newvine, Colleen (8 July 2020). "Eleusis Draws on Research Into Psychedelics To Develop New Medicines for Inflammation". Lucid News - Psychedelics, Consciousness Technology, and the Future of Wellness. Retrieved 16 February 2025.
  7. 1 2 3 4 5 6 7 8 9 Hamilton Morris (14 November 2021). "PODCAST 33: An interview with Dr. Charles D. Nichols". The Hamilton Morris Podcast (Podcast). Patreon. Event occurs at 48:22–53:56. Retrieved 20 January 2025.
  8. ↑ Nichols DE, Johnson MW, Nichols CD (February 2017). "Psychedelics as Medicines: An Emerging New Paradigm". Clin Pharmacol Ther. 101 (2): 209–219. doi:10.1002/cpt.557. PMID   28019026.
  9. ↑ Flanagan TW, Nichols CD (2022). "Psychedelics and Anti-inflammatory Activity in Animal Models". Disruptive Psychopharmacology. Current Topics in Behavioral Neurosciences. Vol. 56. pp. 229–245. doi:10.1007/7854_2022_367. ISBN   978-3-031-12183-8. PMID   35546383.
  10. ↑ Nichols CD (November 2022). "Psychedelics as potent anti-inflammatory therapeutics". Neuropharmacology. 219: 109232. doi: 10.1016/j.neuropharm.2022.109232 . PMID   36007854.
  11. ↑ Flanagan TW, Nichols CD (August 2018). "Psychedelics as anti-inflammatory agents" (PDF). Int Rev Psychiatry. 30 (4): 363–375. doi:10.1080/09540261.2018.1481827. PMID   30102081.
  12. ↑ Thompson C, Szabo A (December 2020). "Psychedelics as a novel approach to treating autoimmune conditions". Immunol Lett. 228: 45–54. doi:10.1016/j.imlet.2020.10.001. hdl: 10852/80687 . PMID   33035575.
  13. ↑ Alexander T. Shulgin; Ann Shulgin (1991). PiHKAL: A Chemical Love Story (1st ed.). Berkeley, CA: Transform Press. ISBN   978-0-9630096-0-9. OCLC   25627628.
  14. 1 2 Lekhtman, Alexander (8 July 2020). "Researcher Charles Nichols Studies the Impact of Psychedelic Substances on Inflammation". Lucid News - Psychedelics, Consciousness Technology, and the Future of Wellness. Retrieved 16 February 2025.
  15. 1 2 Flanagan TW, Billac GB, Landry AN, Sebastian MN, Cormier SA, Nichols CD (April 2021). "Structure-Activity Relationship Analysis of Psychedelics in a Rat Model of Asthma Reveals the Anti-Inflammatory Pharmacophore" (PDF). ACS Pharmacol Transl Sci. 4 (2): 488–502. doi:10.1021/acsptsci.0c00063. PMC   8033619 . PMID   33860179. The nature of the 4-position substituent of phenethylamine psychedelics has been previously linked to 5-HT2 receptor selectivity as well as agonist properties at 5-HT2 receptors.40 Analysis of the 4-position demonstrated that the identity of the moiety at this position was rather flexible. Fully efficacious substitutions at the 4-position included the halogens iodine and bromine (R)-DOI (Figure 3), 2C-B (Figure 7A), methoxy (TMA-2) (Figure 7G), short-chain hydrocarbons (R)-DOM (Figure 7H), (R)-DOET) (Figure 7I), and a branched hydrocarbon (DOiBu) (Figure 7J). [...] In a comparison of PenH-AUC values determined for each drug as a proxy measure of anti-inflammatory efficacy (Figure 8A) to either EC50 or EMax for calcium mobilization downstream of 5- HT2A receptor activation (Table 1), [...]
  16. ↑ Flanagan TW, Billac G, Nichols CD (2022). "Differential Regulation of Inflammatory Responses Following 5-HT 2 Receptor Activation in Pulmonary Tissues". The FASEB Journal. 36 (S1). doi: 10.1096/fasebj.2022.36.S1.R2617 . ISSN   0892-6638.
  17. ↑ Flanagan TW, Foster TP, Galbato TE, Lum PY, Louie B, Song G, et al. (February 2024). "Serotonin-2 Receptor Agonists Produce Anti-inflammatory Effects through Functionally Selective Mechanisms That Involve the Suppression of Disease-Induced Arginase 1 Expression". ACS Pharmacology & Translational Science. 7 (2): 478–492. doi:10.1021/acsptsci.3c00297. PMC   10863441 . PMID   38357283. The effects of (R)-DOTFM were examined in the head-twitch response (HTR) assay. (R)-DOTFM produced a strong HTR with a potent ED 50 of 0.60 μmol/kg. These values are equivalent to (R)-DOI, as previously determined.
  18. ↑ Gunther, Marc (26 October 2022). "What's the Future of Eleusis Therapeutics After Acquisition by Beckley Psytech?". Lucid News - Psychedelics, Consciousness Technology, and the Future of Wellness. Retrieved 17 February 2025.
  19. ↑ "Beckley Psytech Strengthens Pipeline and Development Team With Acquisition of Eleusis Therapeutics Limited". Psychedelic Alpha. Psychedelic Alpha. 24 October 2022. Retrieved 17 February 2025.


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