Chemistry:2C-iBu

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2C-iBu, or 2C-IB, also known as 4-isobutyl-2,5-dimethoxyphenethylamine or 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.[1][2][3][4][5][6] It is a member of the phenethylamine and 2C families of compounds.[3][4][6] The drug is being developed as a topical eye drop for treatment of inflammatory eye conditions.[1][2] There is also interest in 2C-iBu and related drugs for treatment of systemic inflammation and neuroinflammation.[7][8][9][10][11][4]

Use and effects

2C-iBu was not assessed or discovered by Alexander Shulgin and was not described in his 1991 book PiHKAL (Phenethylamines I Have Known and Loved).[6][12] However, he did include 2C-iBu (as "2C-IB") as a DOM analogue in a table in his 2011 book The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds.[13] In addition, Shulgin 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.[13] The cited source for these observations was a 2006 personal communication with M. Mueller.[13]

Interactions

Pharmacology

Pharmacodynamics

2C-iBu activities
Target Affinity (Ki, nM)
2C-iBu (R)-DOI
5-HT1A 79 1,300
5-HT1B 50 2,500
5-HT1D 63 ND
5-HT2A 1.3 0.040
5-HT2B 16 2.5
5-HT2C 0.25 0.63
5-HT6 1,300 ND
5-HT7 320 ND
Notes: The smaller the value, the more avidly the drug interacts with the site. All proteins are human unless otherwise specified. Refs: [3]

2C-iBu is a highly potent and robustly efficacious serotonin 5-HT2A receptor agonist.[3] Its EC50 values are 1.3 nM for calcium mobilization and 57.5 nM for β-arrestin-2 recruitment, whereas its Emax values are 103% for calcium mobilization and 77% for β-arrestin-2 recruitment relative to serotonin.[3] 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.[3] 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.[3]

2C-iBu dose-dependently produces the head-twitch response (HTR), a behavioral proxy of psychedelic effects, in rodents.[3] In terms of ED50, 2C-iBu is about 3-fold less potent than (R)-DOI in producing the HTR.[3] 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.[5][14]

The drug is effective in an allergic asthma model in rodents and showed similar potency as (R)-DOI.[3] 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.[3] 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 4-isobutyl-2,5-dimethoxyphenethylamine, is a phenethylamine and 2C derivative.[3][4][6]

Synthesis

The chemical synthesis of 2C-iBu has been described.[3][13]

Analogues

Related drugs to 2C-iBu include 2C-Bu (the butyl analogue), 2C-tBu (the tert-butyl analogue), 2C-sBu (the sec-butyl analogue), and 2C-CPM (the cyclopropylmethyl analogue).[3] In addition, 2C-iBu is related to DOx drugs such as DOIB (DOiBu).[3][15]

According to Charles D. Nichols, 2,5-dimethoxyamphetamine (2,5-DMA) has potent anti-inflammatory activity with weak or no hallucinogenic effects.[6][15] Moreover, DOTFM has potent psychedelic effects with no anti-inflammatory activity.[6][16][17] Hence, it appears that the anti-inflammatory effects and psychedelic effects of serotonin 5-HT2A receptor agonists can be fully dissociated.[6]

History

2C-iBu was briefly described by Alexander Shulgin in his 2011 book The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds.[13] It was subsequently more thoroughly characterized by Charles D. Nichols and colleagues at Louisiana State University School of Medicine as a novel anti-inflammatory drug in the late 2010s.[3][6] Eleusis has licensed 2C-iBu intellectual property from LSU and the drug has reached the preclinical research stage of development, but no recent development has been reported as of October 2023.[1][2]

Society and culture

Canada

2C-iBu is a controlled substance in Canada under phenethylamine blanket-ban language.[18]

United States

2C-iBu is not a controlled substance in the United States.[5][19]

Research

2C-iBu was developed as a novel anti-inflammatory drug by Charles D. Nichols and colleagues at Eleusis in the late 2010s.[6][3] They are developing it for treatment of inflammatory conditions.[1][2] Eleusis was acquired by and merged into Beckley Psytech in October 2022.[1][20][21] The drug has reached the preclinical research stage of development, but no recent development has been reported as of October 2023.[1][2] Eleusis has licensed intellectual property surrounding 2C-iBu and has patent protection for 2C-iBu.[5][3]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 "ELE 02". 28 October 2023. https://adisinsight.springer.com/drugs/800056031. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 "Delving into the Latest Updates on ELE-02 with Synapse". 23 January 2025. https://synapse.patsnap.com/drug/bd694ba3fc1443a2ba0f5de51a5bebd9. 
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 3.14 3.15 3.16 3.17 Nichols CD, Billac G, Nichols DE, "Compounds and methods for treating inflammatory disorders", WO patent published 2020210823, published 15 October 2020
  4. ↑ 4.0 4.1 4.2 4.3 "Eleusis Drug Development Overview". LSX World Congress 2020. February 2020. https://www.youtube.com/watch?v=VwblUOQQwMI. 
  5. ↑ 5.0 5.1 5.2 5.3 "Eleusis Draws on Research Into Psychedelics To Develop New Medicines for Inflammation". 8 July 2020. https://www.lucid.news/eleusis-research-on-psychedelics-develop-inflammation-medicines/. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 6.8 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.
  7. ↑ "Psychedelics as Medicines: An Emerging New Paradigm". Clin Pharmacol Ther 101 (2): 209–219. February 2017. doi:10.1002/cpt.557. PMID 28019026. 
  8. ↑ "Psychedelics and Anti-inflammatory Activity in Animal Models". Disruptive Psychopharmacology. Current Topics in Behavioral Neurosciences. 56. 2022. pp. 229–245. doi:10.1007/7854_2022_367. ISBN 978-3-031-12183-8. 
  9. ↑ "Psychedelics as potent anti-inflammatory therapeutics". Neuropharmacology 219. November 2022. doi:10.1016/j.neuropharm.2022.109232. PMID 36007854. 
  10. ↑ "Psychedelics as anti-inflammatory agents". Int Rev Psychiatry 30 (4): 363–375. August 2018. doi:10.1080/09540261.2018.1481827. PMID 30102081. http://usdbiology.com/cliff/Courses/Advanced%20Seminars%20in%20Neuroendocrinology/Therapeutic%20Effects%20of%20Psychedelics%2019/Flanagan%20Nichols%2018%20IntRevPsychiatry%20Psychedelics%20as%20anti-inflammatory%20agents.pdf. 
  11. ↑ "Psychedelics as a novel approach to treating autoimmune conditions". Immunol Lett 228: 45–54. December 2020. doi:10.1016/j.imlet.2020.10.001. PMID 33035575. 
  12. ↑ PiHKAL: A Chemical Love Story (1st ed.). Berkeley, CA: Transform Press. 1991. ISBN 978-0-9630096-0-9. OCLC 25627628. https://books.google.com/books?id=O8AdHBGybpcC. 
  13. ↑ 13.0 13.1 13.2 13.3 13.4 "#60. DOM". The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds. 1. Berkeley, CA: Transform Press. 2011. pp. 118–129. ISBN 978-0-9630096-3-0. OCLC 709667010. https://archive.org/details/shulgin-index-vol-1/page/118/mode/1up. "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." 
  14. ↑ 14.0 14.1 "Researcher Charles Nichols Studies the Impact of Psychedelic Substances on Inflammation". 8 July 2020. https://www.lucid.news/researcher-charles-nichols-studies-the-impact-of-psychedelic-substances-on-inflammation/. 
  15. ↑ 15.0 15.1 "Structure-Activity Relationship Analysis of Psychedelics in a Rat Model of Asthma Reveals the Anti-Inflammatory Pharmacophore". ACS Pharmacol Transl Sci 4 (2): 488–502. April 2021. doi:10.1021/acsptsci.0c00063. PMID 33860179. PMC 8033619. https://www.researchgate.net/publication/360537036. "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. ↑ "Differential Regulation of Inflammatory Responses Following 5-HT 2 Receptor Activation in Pulmonary Tissues". The FASEB Journal 36 (S1). 2022. doi:10.1096/fasebj.2022.36.S1.R2617. ISSN 0892-6638. 
  17. ↑ "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. February 2024. doi:10.1021/acsptsci.3c00297. 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. ↑ "Controlled Drugs and Substances Act". https://laws-lois.justice.gc.ca/eng/acts/c-38.8/FullText.html. 
  19. ↑ Orange Book: List of Controlled Substances and Regulated Chemicals (January 2026), United States: U.S. Department of Justice: Drug Enforcement Administration (DEA): Diversion Control Division, January 2026, https://www.deadiversion.usdoj.gov/schedules/orangebook/orangebook.pdf 
  20. ↑ "What's the Future of Eleusis Therapeutics After Acquisition by Beckley Psytech?". 26 October 2022. https://www.lucid.news/eleusis-therapeutics-acquisition-by-beckley-psytech/. 
  21. ↑ "Beckley Psytech Strengthens Pipeline and Development Team With Acquisition of Eleusis Therapeutics Limited". 24 October 2022. https://psychedelicalpha.com/news/beckley-psytech-strengthens-pipeline-and-development-team-with-acquisition-of-eleusis-therapeutics-limited. 



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