Jump to content

Ibogalog

Add links
From Wikipedia, the free encyclopedia
Chemical structure of tabernanthalog (TBG; DLX-007), one of the most well-known ibogalogs.[1]

An ibogalog, or simplified ibogaine analogue, also known as a substituted 1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (or simply substituted hexahydroazepinoindole), is a derivative of noribogaminalog and a simplified analogue of iboga alkaloids and related compounds such as ibogaine.[1][2][3][4] They are tricyclic cyclized tryptamines and are closely related to the β-carbolines or harmala alkaloids.[1][2][4] However, ibogalogs have a mostly-hydrogenated 7-membered azepine ring instead of the variably-saturated 6-membered pyridine ring present in β-carbolines.[1][2] Relative to the iboga alkaloids, ibogalogs retain the indole and hydrogenated azepine rings, but the isoquinuclidine (2-azabicyclo[2.2.2]octane) ring system has been removed, simplifying the chemical structure.[1][4]

Ibogalogs are known to act as potent serotonin 5-HT2A and 5-HT2C receptor agonists, as well as acting as agonists of other serotonin receptors.[2][4][5] This is in contrast to iboga alkaloids like ibogaine and noribogaine, which are inactive as serotonin receptor agonists.[1] Ibogalogs also possess other actions, such as serotonin 5-HT2B receptor antagonism or partial agonism,[2] monoamine reuptake inhibition,[2] and nicotinic acetylcholine receptor inhibition.[6][7] Unlike iboga alkaloids like noribogaine, they show no opioid receptor agonism.[1] In addition, the compounds have dramatically reduced potency at the hERG antitarget compared to ibogaine, which confers much less cardiotoxicity.[1][4]

Ibogalogs have been reported to produce psychoplastogenic,[2][1] antidepressant-like,[2][1] anxiolytic-like,[8] sedative-like,[8][9] antiaddictive-like,[1][10] and analgesic effects in animals.[11][12] Based on the rodent head-twitch response, a behavioral proxy of serotonergic psychedelic activity, ibogainalog may produce psychedelic effects in humans, while other assessed ibogainalogs, including tabernanthalog, ibogaminalog, noribogainalog, and catharanthalog, appear to be non-psychedelic.[1][8][12][4] In addition, PNU-22394 was non-hallucinogenic in clinical studies.[5]

Ibogalogs, such as PNU-22394, were first developed and described in the 1960s.[9][13] In the early 2000s, ibogalogs like PNU-22394 were studied and described further as potential appetite suppressants and weight loss drugs.[14][5][15] Subsequently, ibogalogs were studied and described in the early 2020s and thereafter, including by David E. Olson and colleagues at the University of California, Davis and Delix Therapeutics, as potential treatments of central nervous system disorders.[16][1][2] Relatedly, tabernanthalog (TBG; DLX-007) is under development for potential medical use.[1][17][18]

List of ibogalogs

[edit]
Structure Name Synonyms Chemical name Iboga analogue Ref
Noribogaminalog 1,2,3,4,5,6-hexahydroazepino[4,5-b]indole Noribogamine [13]
Ibogaminalog DM-506 3-methyl-2,4,5,6-tetrahydro-1H-azepino[4,5-b]indole Ibogamine
Noribogainalog Nor-IBG 9-hydroxy-3-methyl-2,4,5,6-tetrahydro-1H-azepino[4,5-b]indole Noribogaine
Ibogainalog IBG 9-methoxy-3-methyl-2,4,5,6-tetrahydro-1H-azepino[4,5-b]indole Ibogaine [1]
Tabernanthalog TBG; DLX-007 8-methoxy-3-methyl-2,4,5,6-tetrahydro-1H-azepino[4,5-b]indole Tabernanthine [1]
Catharanthalog CAG methyl 3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-5-carboxylate Catharanthine [19][12]
Fluorogainalog 9-fluoro-3-methyl-2,4,5,6-tetrahydro-1H-azepino[4,5-b]indole [20][21]
LS-22925 9-fluoro-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole [22]
PNU-22394 U-22394 6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole [14][15]
[edit]
Structure Name Synonyms Chemical name Ref
PHA-57378 2,7,8,9,10,11-hexahydro-1H-azepino[4,5-b][1,4]oxazino[2,3,4-hi]indole
PNU-181731 2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole

See also

[edit]

References

[edit]
  1. ^ a b c d e f g h i j k l m n o p Cameron LP, Tombari RJ, Lu J, Pell AJ, Hurley ZQ, Ehinger Y, Vargas MV, McCarroll MN, Taylor JC, Myers-Turnbull D, Liu T, Yaghoobi B, Laskowski LJ, Anderson EI, Zhang G, Viswanathan J, Brown BM, Tjia M, Dunlap LE, Rabow ZT, Fiehn O, Wulff H, McCorvy JD, Lein PJ, Kokel D, Ron D, Peters J, Zuo Y, Olson DE (January 2021). "A non-hallucinogenic psychedelic analogue with therapeutic potential". Nature. 589 (7842): 474–479. Bibcode:2021Natur.589..474C. doi:10.1038/s41586-020-3008-z. PMC 7874389. PMID 33299186.
  2. ^ a b c d e f g h i Arias HR, Rudin D, Luethi D, Valenta J, Leśniak A, Czartoryska Z, Olejarz-Maciej A, Doroz-Płonka A, Manetti D, De Deurwaerdère P, Romanelli MN, Handzlik J, Liechti ME, Chagraoui A (January 2025). "The psychoplastogens ibogaminalog and ibogainalog induce antidepressant-like activity in naïve and depressed mice by mechanisms involving 5-HT2A receptor activation and serotonergic transmission". Prog Neuropsychopharmacol Biol Psychiatry. 136 111217. doi:10.1016/j.pnpbp.2024.111217. PMID 39662723.
  3. ^ Iyer RN, Favela D, Zhang G, Olson DE (March 2021). "The iboga enigma: the chemistry and neuropharmacology of iboga alkaloids and related analogs". Nat Prod Rep. 38 (2): 307–329. doi:10.1039/d0np00033g. PMC 7882011. PMID 32794540.
  4. ^ a b c d e f Zięba A, Stępnicki P, Matosiuk D, Kaczor AA (December 2021). "Overcoming Depression with 5-HT2A Receptor Ligands". International Journal of Molecular Sciences. 23 (1): 10. doi:10.3390/ijms23010010. PMC 8744644. PMID 35008436.
  5. ^ a b c Fitzgerald, Lawrence W; Ennis, Michael D (2002). "Chapter 3: 5-HT2C receptor modulators: Progress in development of new CNS medicines". Annual Reports in Medicinal Chemistry. Vol. 37. Elsevier. pp. 21–30. doi:10.1016/s0065-7743(02)37004-0. ISBN 978-0-12-040537-4. The closely related azepinoindole 11 (PNU-22394) has been described as a 5-HT2C agonist (Ki = 18.8 nM, 83% efficacy) that has recently been reported to decrease feeding in rats and produce a weight loss in humans (68). Although dose-related clinical side effects observed included headache, anxiety, nausea, and vomiting, these effects were dramatically reduced following four days of dosing. No hallucinations were observed despite the fact that 11 is also a potent, high efficacy 5-HT2A agonist (5-HT2A Ki = 19 nM, 64% efficacy). Compound 11 also has excellent affinity at 5-HT2B receptors (Ki = 28.5 nM).
  6. ^ Tae, Han-Shen; Ortells, Marcelo O.; Tekarli, Bassel J.; Manetti, Dina; Romanelli, Maria Novella; McIntosh, J. Michael; Adams, David J.; Arias, Hugo R. (19 July 2023). "DM506 (3-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5- b ]indole fumarate), a Novel Derivative of Ibogamine, Inhibits α7 and α9α10 Nicotinic Acetylcholine Receptors by Different Allosteric Mechanisms". ACS Chemical Neuroscience. 14 (14): 2537–2547. doi:10.1021/acschemneuro.3c00212. ISSN 1948-7193. PMID 37386821. Retrieved 28 July 2025.
  7. ^ Tae HS, Ortells MO, Yousuf A, Xu SQ, Akk G, Adams DJ, Arias HR (May 2024). "Tabernanthalog and ibogainalog inhibit the α7 and α9α10 nicotinic acetylcholine receptors via different mechanisms and with higher potency than the GABAA receptor and CaV2.2 channel". Biochem Pharmacol. 223 116183. doi:10.1016/j.bcp.2024.116183. PMC 11151864. PMID 38580167.
  8. ^ a b c Arias, Hugo R.; Rudin, Deborah; Hines, Dustin J.; Contreras, April; Gulsevin, Alican; Manetti, Dina; Anouar, Youssef; De Deurwaerdere, Philippe; Meiler, Jens; Romanelli, Maria Novella; Liechti, Matthias E.; Chagraoui, Abdeslam (2024). "The novel non-hallucinogenic compound DM506 (3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole) induces sedative- and anxiolytic-like activity in mice by a mechanism involving 5-HT2A receptor activation" (PDF). European Journal of Pharmacology. 966 176329. doi:10.1016/j.ejphar.2024.176329. PMID 38253116. Retrieved 28 July 2025.
  9. ^ a b Brimblecombe RW, Pinder RM (1975). "Indolealkylamines and Related Compounds". Hallucinogenic Agents. Bristol: Wright-Scientechnica. pp. 98–144. ISBN 978-0-85608-011-1. OCLC 2176880. OL 4850660M. The iboga alkaloids are long overdue for a detailed examination of their psychic effects in man. It is interesting that simplification of the iboga structure to give the hexahydroazepino[4,5-b]indoles (for example, 4.42) enhances the tryptamine-like properties, at least as far as tremorogenic activity is concerned, but also enhances the sedative effects. Thus, these compounds have chlorpromazine-like properties in both man and animals (Hester, Tang, Keesling, and Veldkamp, 1968).
  10. ^ Heinsbroek JA, Giannotti G, Bonilla J, Olson DE, Peters J (June 2023). "Tabernanthalog Reduces Motivation for Heroin and Alcohol in a Polydrug Use Model". Psychedelic Med (New Rochelle). 1 (2): 111–119. doi:10.1089/psymed.2023.0009. PMC 10286262. PMID 37360328.
  11. ^ Arias HR, Micheli L, Rudin D, Bento O, Borsdorf S, Ciampi C, Marin P, Ponimaskin E, Manetti D, Romanelli MN, Ghelardini C, Liechti ME, Di Cesare Mannelli L (August 2024). "Non-hallucinogenic compounds derived from iboga alkaloids alleviate neuropathic and visceral pain in mice through a mechanism involving 5-HT2A receptor activation". Biomed Pharmacother. 177 116867. doi:10.1016/j.biopha.2024.116867. PMID 38889634.
  12. ^ a b c Arias HR, Micheli L, Jensen AA, Galant S, Vandermoere F, Venturi D, Manetti D, Romanelli MN, Ghelardini C, Marin P, Di Cesare Mannelli L (March 2025). "Ibogalogs decrease neuropathic pain in mice through a mechanism involving crosstalk between 5-HT2A and mGlu2 receptors". Biomed Pharmacother. 184 117887. doi:10.1016/j.biopha.2025.117887. PMID 39938347.
  13. ^ a b Hester JB, Tang AH, Keasling HH, Veldkamp W (January 1968). "Azepinoindoles. I. Hexahydroazepino[4,5-b]indoles". J Med Chem. 11 (1): 101–106. doi:10.1021/jm00307a023. PMID 5637151.
  14. ^ a b McCall, R. B., Franklin, S. R., Hyslop, D. K., Knauer, C. S., Chio, C. L., Haber, C. L., & Fitzgerald, L. W. (2001). PNU-22394, a 5-HT2C receptor agonist, reduces feeding in rodents and produces weight loss in humans. In Soc Neurosci Abstr (Vol. 27, No. 309.2). https://scholar.google.com/scholar?cluster=17067737110870651783
  15. ^ a b Bishop, Michael J; Nilsson, Björn M (2003). "New 5-HT2C receptor agonists". Expert Opinion on Therapeutic Patents. 13 (11): 1691–1705. doi:10.1517/13543776.13.11.1691. ISSN 1354-3776. Retrieved 28 July 2025.
  16. ^ Extance, Andy; Extance, Andy; McVean, Ada; Robinson, Julia; Welter, Kira; Durrani, Jamie; Extance, Andy (17 December 2020). "Chemists tame shamanic addiction treatment". Chemistry World. Retrieved 28 July 2025.
  17. ^ "DLX 7". AdisInsight. 20 February 2023. Retrieved 18 November 2024.
  18. ^ "Delving into the Latest Updates on DLX-7 with Synapse". Synapse. 7 November 2024. Retrieved 18 November 2024.
  19. ^ "Methyl 3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-5-carboxylate". PubChem. Retrieved 28 July 2025.
  20. ^ "9-fluoro-3-methyl-2,4,5,6-tetrahydro-1H-azepino[4,5-b]indole". PubChem. Retrieved 28 July 2025.
  21. ^ Sutton C, Williams EQ, Homsi H, Beerepoot P, Nazari R, Han D, Ramsey AJ, Mash DC, Olson DE, Blough B, Salahpour A (2022). "Structure-Activity Relationships of Dopamine Transporter Pharmacological Chaperones". Front Cell Neurosci. 16 832536. doi:10.3389/fncel.2022.832536. PMC 9124866. PMID 35614973.
  22. ^ "9-Fluoro-1,2,3,4,5,6-hexahydro-azepino(4,5-b)indole". PubChem. Retrieved 28 July 2025.


Retrieved from "https://en.wikipedia.org/w/index.php?title=Ibogalog&oldid=1303645803"