IsoDMT

Last updated

isoDMT
IsoDMT.svg
Clinical data
Other namesiso-DMT; N,N-Dimethylisotryptamine; iso-N,N-DMT; N,N-Dimethylaminoisotryptamine; Dimethylaminoisotryptamine
Drug class Non-hallucinogenic serotonin 5-HT2A receptor agonist; Psychoplastogen
Identifiers
  • 2-indol-1-yl-N,N-dimethylethanamine
CAS Number
PubChem CID
ChemSpider
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C12H16N2
Molar mass 188.274 g·mol−1
3D model (JSmol)
  • CN(C)CCN1C=CC2=CC=CC=C21
  • InChI=1S/C12H16N2/c1-13(2)9-10-14-8-7-11-5-3-4-6-12(11)14/h3-8H,9-10H2,1-2H3
  • Key:PSHKCPACSIZILK-UHFFFAOYSA-N

isoDMT, also known as N,N-dimethylisotryptamine, is a putatively non-hallucinogenic serotonin 5-HT2A receptor agonist and psychoplastogen of the isotryptamine group. [1] [2] [3] [4] [5] [6] It is the isotryptamine homologue of dimethyltryptamine (DMT), a more well-known serotonergic psychedelic of the tryptamine family, and represents a small structural modification of DMT. [2] [3] [6]

Contents

Pharmacology

The drug does not produce hallucinogen-like stimulus generalization in animal drug discrimination tests and similarly does not produce the head-twitch response, an animal behavioral proxy of psychedelic-like effects. [1] [2] [4] [6] As such, it is not expected to be hallucinogenic in humans. [1] [2] [4] [6] However, isoDMT retains significant activity at the serotonin 5-HT2 receptors and shows psychoplastogenic effects comparable to those of serotonergic psychedelics in preclinical research. [7] [6] [8] [9] Its affinities (Ki) for the serotonin 5-HT2 receptors have been reported to be 600–650 nM for 5-HT2A and 720 nM at 5-HT2C. [9]

Analogs

Several derivatives of isoDMT have been developed, including the non-hallucinogenic psychoplastogens 5-MeO-isoDMT and zalsupindole (DLX-001; AAZ-A-154; (R)-5-MeO-α-methyl-isoDMT) and the hallucinogen and psychoplastogen 6-MeO-isoDMT. [1] [10] [7] [6] Zalsupindole has shown antidepressant-like effects in animals, thought to be secondary to its psychoplastogenic actions, and is under development for potential medical use to treat neuropsychiatric disorders like depression. [1] [11] [12] [13] Another analogue of isoDMT is α-methylisotryptamine (isoAMT), the isotryptamine homologue of α-methyltryptamine (AMT). [14] [15] [16]

History

isoDMT and its derivatives were first described in the scientific literature by 1984. [1] [8] [10] They were subsequently further characterized in 2020. [7] [6]

See also

References

  1. 1 2 3 4 5 6 Duan W, Cao D, Wang S, Cheng J (January 2024). "Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants". Chemical Reviews. 124 (1): 124–163. doi:10.1021/acs.chemrev.3c00375. PMID   38033123. The isoDMT derivatives, first introduced in [1984] by Glennon et al., also represent a group of nonhallucinogenic 5-HT2AR agonists. For example, compounds isoDMT (22) and 5-OMe-isoDMT (24) have been identified as nonhallucinogenic in the drug discrimination test.139 Along that line, the Olson group [in 2020] reported a series of isoDMT compounds as a family of psychoplastogens, being able to promote neuronal growth.143 [...] they have identified compound AAZ-A-154 (31) as a nonhallucinogenic compound [and derivative of isoDMT and 5-MeO-isoDMT] with significant antidepressant effects in mouse models.105
  2. 1 2 3 4 Sotille R, Singh H, Weisman A, Vida T (May 2022). "Unraveling the Mysteries of Mental Illness With Psilocybin". Cureus. 14 (5): e25414. doi: 10.7759/cureus.25414 . PMC   9233936 . PMID   35769681. Proof-of-concept experiments have been successful at structurally transforming ibogaine to tabernanthalog (TBG) [88] and DMT to isoDMT[89]. Both TBG and isoDMT promote neuroplasticity and have anti-addictive and behavioral effects, respectively. Further, both TBG and isoDMT do not induce a head-twitch response in rodents, which correlates well with the hallucinogenic properties of true psychedelics like LSD and psilocin [90].
  3. 1 2 Kwan AC, Olson DE, Preller KH, Roth BL (November 2022). "The neural basis of psychedelic action". Nature Neuroscience. 25 (11): 1407–1419. doi:10.1038/s41593-022-01177-4. PMC   9641582 . PMID   36280799. Parallel efforts to improve the scalability of psychedelic-like therapeutics have focused on engineering compounds that lack hallucinogenic/perceptual effects but maintain sustained therapeutic efficacy after a single dose64. [...] Initial work in this area has focused on developing non-hallucinogenic entities (also referred to as non-hallucinogenic psychoplastogens65), such as isoDMT66, TBG67, and AAZ12 by slightly modifying the structures of known hallucinogenic compounds (Figure 1c).
  4. 1 2 3 Atiq MA, Baker MR, Voort JL, Vargas MV, Choi DS (May 2024). "Disentangling the acute subjective effects of classic psychedelics from their enduring therapeutic properties". Psychopharmacology. doi: 10.1007/s00213-024-06599-5 . PMID   38743110. Structure–activity relationship (SAR) studies and the redesigning of traditional psychedelics has provided numerous candidate molecules that demonstrate the desired phenotype: lacking hallucinogenic properties but retaining therapeutic value. Dunlap et al. explored this strategy by identifying key features of the psychoplastogen pharmacophore (dimethyltryptamine, DMT) and engineering its derivatives ('isoDMT') capable of dendritogenesis, while lacking HTR responses in mice (Dunlap et al. 2020).
  5. ↑ Banushi B, Polito V (October 2023). "A Comprehensive Review of the Current Status of the Cellular Neurobiology of Psychedelics". Biology. 12 (11): 1380. doi: 10.3390/biology12111380 . PMC   10669348 . PMID   37997979. However, recent findings suggest that the TrkB-dependent effects of psychedelics on plasticity may be separated from their hallucinogenic-like effects mediated by 5-HT2A receptors [51,199,200]. This suggests the potential to discover compounds or treatment combinations that retain some of the antidepressant effects of psychedelics without the hallucinogenic effects [62,201]. Some of these compounds include isoDMT [202], tabernanthalog [199], AAZ-A-154 [203], and 2-bromo-LSD [204], achieved by modifying the structures of known hallucinogenic compounds.
  6. 1 2 3 4 5 6 7 Dunlap LE, Azinfar A, Ly C, Cameron LP, Viswanathan J, Tombari RJ, et al. (February 2020). "Identification of Psychoplastogenic N,N-Dimethylaminoisotryptamine (isoDMT) Analogues through Structure-Activity Relationship Studies". Journal of Medicinal Chemistry. 63 (3): 1142–1155. doi:10.1021/acs.jmedchem.9b01404. PMC   7075704 . PMID   31977208.
  7. 1 2 3 Dunlap LE (2022). "Development of Non-Hallucinogenic Psychoplastogens". eScholarship. Retrieved 19 November 2024.
  8. 1 2 Glennon RA, Jacyno JM, Young R, McKenney JD, Nelson D (January 1984). "Synthesis and evaluation of a novel series of N,N-dimethylisotryptamines". Journal of Medicinal Chemistry. 27 (1): 41–45. doi:10.1021/jm00367a008. PMID   6581313.
  9. 1 2 Chang-Fong J, Addo J, Dukat M, Smith C, Mitchell NA, Herrick-Davis K, et al. (January 2002). "Evaluation of isotryptamine derivatives at 5-HT(2) serotonin receptors". Bioorg Med Chem Lett. 12 (2): 155–158. doi:10.1016/s0960-894x(01)00713-2. PMID   11755343.
  10. 1 2 Glennon RA, Young R (1987). "The Study of Structure-Activity Relationships Using Drug Discrimination Methodology". Methods of Assessing the Reinforcing Properties of Abused Drugs. New York, NY: Springer New York. pp. 373–390. doi:10.1007/978-1-4612-4812-5_18. ISBN   978-1-4612-9163-3.
  11. ↑ Rasmussen K, Engel S, Chytil M, Koenig A, Meyer R, Rus M, et al. (December 2023). "ACNP 62nd Annual Meeting: Poster Abstracts P251 - P500: P361. Preclinical Pharmacology of DLX-001, a Novel Non-Hallucinogenic Neuroplastogen With the Potential for Treating Neuropsychiatric Diseases". Neuropsychopharmacology. 48 (Suppl 1): 211–354 (274–275). doi:10.1038/s41386-023-01756-4. PMC   10729596 . PMID   38040810.
  12. ↑ "DLX 1". AdisInsight. 11 December 2023. Retrieved 2 November 2024.
  13. ↑ "Delving into the Latest Updates on DLX-001 with Synapse". Synapse. 1 November 2024. Retrieved 2 November 2024.
  14. ↑ Bauer CT (5 July 2014). Determinants of Abuse-Related Effects of Monoamine Releasers in Rats. VCU Scholars Compass (Thesis). doi:10.25772/AN08-SZ65 . Retrieved 24 November 2024.
  15. ↑ Banks ML, Bauer CT, Blough BE, Rothman RB, Partilla JS, Baumann MH, et al. (June 2014). "Abuse-related effects of dual dopamine/serotonin releasers with varying potency to release norepinephrine in male rats and rhesus monkeys". Experimental and Clinical Psychopharmacology. 22 (3): 274–284. doi:10.1037/a0036595. PMC   4067459 . PMID   24796848.
  16. ↑ Lyon RA, Titeler M, Seggel MR, Glennon RA (January 1988). "Indolealkylamine analogs share 5-HT2 binding characteristics with phenylalkylamine hallucinogens". European Journal of Pharmacology. 145 (3): 291–297. doi:10.1016/0014-2999(88)90432-3. PMID   3350047.
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