Chemistry:BOL-148

From HandWiki

BOL-148, also known as 2-bromo-LSD or as bromolysergide, is a non-hallucinogenic serotonin receptor modulator of the lysergamide family related to the psychedelic drug lysergic acid diethylamide (LSD).[1][2][3][4] It is specifically the 2-bromo derivative of LSD.[2][3]

The drug is a non- or minimally-hallucinogenic serotonin 5-HT2A receptor partial agonist, as well as acting at other targets such as other serotonin receptors and dopamine receptors.[1][2] The lack of psychedelic effects with BOL-148 is thought to be due to lower-efficacy partial agonism at the serotonin 5-HT2A receptor compared to LSD that is insufficient to produce hallucinogenic effects.[2] The drug has been found to produce psychoplastogenic and antidepressant-like effects in animals.[1][2]

BOL-148 was initially developed by Albert Hofmann in the 1950s, as part of the original research from which LSD was also derived.[2][1][5] It is now being reinvestigated and is under development for the potential treatment of cluster headaches and other conditions.[6][7][4] This is under new developmental code names including BETR-001, TD-0148A, and NYPRG-101.[6][7]

Use and effects

Clinical studies have found that unlike LSD, BOL-148 lacks hallucinogenic effects in humans at doses considered to be moderate to high.[8][9] In addition, some but not all clinical studies of BOL-148 in combination with LSD have found BOL-148 to block the psychedelic effects of LSD.[8]


Interactions

Pharmacology

Pharmacodynamics

BOL-148 was found to be inactive as a psychedelic and so was comparatively little researched for many years, although its similar behaviour in the body made it useful for radiolabelling studies. It was found to bind to many of the same receptors as LSD, but acting as a neutral antagonist rather than an agonist.[10][11] BOL-148 reportedly attenuates the effects of LSD in humans.[12][13]

In 2023, BOL-148 was characterised as a non-hallucinogenic serotonin 5-HT2A receptor biased partial agonist and as a serotonin 5-HT2B receptor antagonist.[1] It shows weaker partial agonism of the serotonin 5-HT2A receptor than LSD (Emax = 60% vs. 92%, respectively).[1] Unlike LSD, BOL-148 fails to produce the head-twitch response, a behavioural proxy of psychedelic effects, in animals.[1][14] In addition, BOL-148 blocked the head-twitch response of the psychedelic DOI.[1]

BOL-148 shows weak recruitment of β-arrestin2 and has reduced potential to induce tolerance in the form of serotonin 5-HT2A receptor downregulation.[1] Similarly to LSD, the drug was also found to interact with numerous other serotonin receptors and targets.[1] However, BOL-148 reportedly shows less off-target activity compared to LSD.[1] In animals, BOL-148 shows psychoplastogenic (i.e., neuroplasticity-enhancing) effects and antidepressant-like effects.[1][15]

The cryo-EM structures of the serotonin 5-HT2A receptor with BOL-148, as well as with various serotonergic psychedelics and other serotonin 5-HT2A receptor agonists, have been solved and published by Bryan L. Roth and colleagues.[16][17]

Chemistry

Analogues

Analogues of BOL-148 (2-bromo-LSD) include 2-iodo-LSD (IOL, MBL-61 (MOB-61; 1-methyl-2-bromo-LSD), 1-methyl-2-iodo-LSD (MIL), 2-oxo-LSD, and bromocriptine, among others. 1P-BOL-148 (1-propionyl-2-bromo-LSD; SYN-L-017) is an ester prodrug of BOL-148.

Development

The generally similar behaviour of BOL-148 to LSD in some respects has shown to be very useful in potential the treatment of cluster headaches.[18] These debilitating attacks have been known for some time to be amenable to treatment with certain hallucinogenic drugs such as LSD and psilocybin, but because of the illegal status of these drugs and the kind of mental changes they induce, research into their medical use has been slow and therapeutic application limited to very specific circumstances under strict supervision. It had been thought that this specific therapeutic action against cluster headaches was limited to hallucinogenic drugs of this type, and would always present a major barrier to their clinical use. However, a serendipitous discovery found that BOL-148 can also produce this therapeutic effect, despite lacking the other effects of LSD. This has led to a resurgence of interest and research into BOL-148 and its possible medical uses. BOL-148, under the developmental code name BETR-001 (previously TD-0148A), is under development by BetterLife Pharma for the treatment of cluster headaches and other indications.[6][7] A prodrug of BOL-148, under the developmental code name SPT-348, is also under development by Seaport Therapeutics for the treatment of depression, anxiety, and other neuropsychiatric disorders.[19][20][21][22]

See also

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 "A non-hallucinogenic LSD analog with therapeutic potential for mood disorders". Cell Rep 42 (3). March 2023. doi:10.1016/j.celrep.2023.112203. PMID 36884348. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 "Beyond the 5-HT2A Receptor: Classic and Nonclassic Targets in Psychedelic Drug Action". J Neurosci 43 (45): 7472–7482. November 2023. doi:10.1523/JNEUROSCI.1384-23.2023. PMID 37940583. 
  3. ↑ 3.0 3.1 "Chemistry/structural biology of psychedelic drugs and their receptor(s)". Br J Pharmacol. October 2024. doi:10.1111/bph.17361. PMID 39354889. 
  4. ↑ 4.0 4.1 "Psychedelics as preventive treatment in headache and chronic pain disorders". Neuropharmacology 215. September 2022. doi:10.1016/j.neuropharm.2022.109166. PMID 35718005. 
  5. ↑ "Substitutionen am Ringsystem der Lysergsäure. III. Halogenierung. 45. Mitteilung über Mutterkornalkaloide". Helvetica Chimica Acta 40 (7): 2160–2170. 1957. doi:10.1002/hlca.19570400716. Bibcode: 1957HChAc..40.2160T. 
  6. ↑ 6.0 6.1 6.2 "BETR 001". 29 August 2024. https://adisinsight.springer.com/drugs/800061475. 
  7. ↑ 7.0 7.1 7.2 "Delving into the Latest Updates on Bromolysergide with Synapse". 14 October 2024. https://synapse.patsnap.com/drug/3bcabbea8776452d8fcd680529dec52c. 
  8. ↑ 8.0 8.1 "Are the LSD-analogs lisuride and ergotamine examples of non-hallucinogenic serotonin 5-HT2A receptor agonists?". Journal of Psychopharmacology 39 (9): 889–895. May 2025. doi:10.1177/02698811251330741. PMID 40322975. 
  9. ↑ Fanchamps, A. (1978). "Some Compounds With Hallucinogenic Activity". Ergot Alkaloids and Related Compounds. Berlin, Heidelberg: Springer Berlin Heidelberg. pp. 567–614. doi:10.1007/978-3-642-66775-6_8. ISBN 978-3-642-66777-0. http://link.springer.com/10.1007/978-3-642-66775-6_8. Retrieved 30 June 2025. 
  10. ↑ "Prevention of psychological effects of d-lysergic acid diethylamide (LSD 25) by its 2-brom derivative (BOL 148)". Nature 178 (4526): 210. July 1956. doi:10.1038/178210a0. PMID 13348662. Bibcode: 1956Natur.178..210G. 
  11. ↑ "Cross tolerance between D-2-brom-lysergic acid diethylamide (BOL-148) and the D-diethylamide of lysergic acid (LSD-25)". Psychopharmacologia 1 (2): 109–116. November 1959. doi:10.1007/bf00409110. PMID 14405871. 
  12. ↑ "Serotonin and the psychedelics". The Serotonin System. 2019. pp. 193–202. doi:10.1016/B978-0-12-813323-1.00011-6. ISBN 978-0-12-813323-1. 
  13. ↑ "Is BOL-148 hallucinogenic?". Cephalalgia 31 (5): 634; author reply 635-634; author reply 636. April 2011. doi:10.1177/0333102410392069. PMID 21163816. 
  14. ↑ "A possible correlation between drug-induced hallucinations in man and a behavioural response in mice". Psychopharmacologia 11 (1): 65–78. 1967. doi:10.1007/BF00401509. PMID 5302272. 
  15. ↑ "ACNP 61st Annual Meeting: Poster Abstracts P271-P540: P358. A Non-Hallucinogenic LSD Analog With Therapeutic Potential for Mood Disorders". Neuropsychopharmacology 47 (Suppl 1): 220–370 (269–270). December 2022. doi:10.1038/s41386-022-01485-0. PMID 36456694. 
  16. ↑ "The structural diversity of psychedelic drug actions revealed". Nature Communications 16 (1). March 2025. doi:10.1038/s41467-025-57956-7. PMID 40108183. Bibcode: 2025NatCo..16.2734G. 
  17. ↑ "Structures of Hallucinogenic and Non-Hallucinogenic Analogues of the 5-HT2A Receptor Reveals Molecular Insights into Signaling Bias". University of North Carolina at Chapel Hill Department of Pharmacology Research Retreat September 16th, 2022 – William and Ida Friday Center. September 2022. https://www.med.unc.edu/pharm/wp-content/uploads/sites/930/2022/07/COMPLETE-PHARM-RETREAT-PROGRAM-2022-UPDATE.pdf#page=37. 
  18. ↑ "The non-hallucinogen 2-bromo-lysergic acid diethylamide as preventative treatment for cluster headache: an open, non-randomized case series". Cephalalgia 30 (9): 1140–1144. September 2010. doi:10.1177/0333102410363490. PMID 20713566. 
  19. ↑ "Delving into the Latest Updates on SPT-348 with Synapse". 8 May 2025. https://synapse.patsnap.com/drug/44317b21afa54ef8b9941975d7bf7f45. 
  20. ↑ "Next-generation psychedelics: should new agents skip the trip?". Nat Biotechnol 42 (6): 827–830. June 2024. doi:10.1038/s41587-024-02285-1. PMID 38831049. "Table 1 | Selected companies working on next-generation psychedelic therapeutics [...] Delix's Boston neighbor Seaport is also developing neuroplastogens, along with other compounds, to treat depression and anxiety disorders. "Our particular play is based on the notion that you don't need a psychedelic trip experience to gather the beneficial effects of these psychedelic agents," says founder and board chair Steve Paul. One of the company's preclinical antidepressants is a non-hallucinogenic LSD analog called SPT-348. LSD itself is a 5-HT2A agonist, but there is a lot of variation between patients in how quickly it is metabolized in the liver, making it challenging to determine the optimal dose. So Seaport has tethered its LSD analog to a novel drug delivery system called Glyph that helps the drug to circumvent the liver. The drug is attached via a linker to a triglyceride, which is absorbed through the gastrointestinal lymphatic system just like dietary fats and passes directly into the bloodstream before breaking down to release the drug. Classical psychedelic drugs are challenging to blind with a placebo in a clinical trial, but SPT348 should be able avoid that difficulty. "Since we don't have a psychedelic experience, the idea is you could do a real placebo-controlled trial, which I think is helpful," says Paul.". 
  21. ↑ Psychedelic Alpha (1 May 2025). "March & April 2025 Psychedelic Patent Update: Lykos' Patent Woes Continue; Filings Provide First Look at Seaport's 2-Bromo-LSD Program; Delix's Ergoline Analogues; CaaMTech's Spinout". https://psychedelicalpha.com/news/march-filings-provide-first-look-at-seaports-2-bromo-lsd-program-delixs-ergoline-analogues-caamtechs-spinout. "Patent Filings Provide First Look At Seaport Therapeutics' SPT-348 (2-Bromo-LSD) Program [...]" 
  22. ↑ "New lipid prodrugs of bromolysergide disclosed in Seaport Therapeutics patent". 11 May 2025. https://www.bioworld.com/articles/719964-new-lipid-prodrugs-of-bromolysergide-disclosed-in-seaport-therapeutics-patent?v=preview. "Seaport Therapeutics Inc. has divulged lipid prodrugs of bromolysergide reported to be useful for the treatment of cluster headache and mood disorder. [...] It hydrolyzed to active compound (release of 2-bromo-LSD>25%) in human plasma. [...]" 

Template:Psychedelics



Retrieved from "https://handwiki.org/wiki/index.php?title=Chemistry:BOL-148&oldid=4035922"