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 AAZ-A-154 (DLX-001; (R)-5-MeO-α-methyl-isoDMT) and the hallucinogen and psychoplastogen 6-MeO-isoDMT. [1] [10] [7] [6] AAZ-A-154 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

Related Research Articles

<span class="mw-page-title-main">Serotonin receptor agonist</span> Neurotransmission-modulating substance

A serotonin receptor agonist is an agonist of one or more serotonin receptors. They activate serotonin receptors in a manner similar to that of serotonin, a neurotransmitter and hormone and the endogenous ligand of the serotonin receptors.

<span class="mw-page-title-main">Ariadne (drug)</span> Psychoactive phenethylamine drug

Ariadne, also known chemically as 4C-D or 4C-DOM, by its developmental code name BL-3912, and by its former tentative brand name Dimoxamine, is a little-known psychoactive drug of the phenethylamine, amphetamine, and phenylisobutylamine families. It is a homologue of the psychedelics 2C-D and DOM.

<span class="mw-page-title-main">AL-34662</span> Chemical compound

AL-34662 is an indazole derivative drug that is being developed for the treatment of glaucoma. It acts as a selective serotonin 5-HT2 receptor agonist, including of the 5-HT2A, 5-HT2B, and 5-HT2C receptors (affinity (IC50Tooltip half-maximal inhibitory concentration) = 14.5, 8.1, and 3.0 nM, respectively). The serotonin 5-HT2A receptor is the same target as that of psychedelic drugs like psilocin. Unlike these drugs however, AL-34662 was designed specifically as a peripherally selective drug, which does not cross the blood–brain barrier. This means that AL-34662 can exploit a useful side effect of the hallucinogenic 5-HT2A receptor agonists, namely reduction in intra-ocular pressure and hence relief from the symptoms of glaucoma, but without causing the psychedelic effects that make centrally active serotonin 5-HT2A receptor agonists unsuitable for clinical use. In animal studies, AL-34662 has been shown to be potent and effective in the treatment of symptoms of glaucoma, with minimal side effects.

5-Methoxy-7,<i>N</i>,<i>N</i>-trimethyltryptamine Chemical compound

5-Methoxy-7,N,N-trimethyltryptamine (5-MeO-7,N,N-TMT, 5-MeO-7-TMT), is a tryptamine derivative which acts as a partial agonist at the 5-HT2 serotonin receptors, with an EC50 of 63.9 nM and an efficacy of 66.2% at 5-HT2A (vs 5-HT), and weaker activity at 5-HT2B and 5-HT2C. In animal tests, both 7,N,N-TMT and 5-MeO-7,N,N-TMT produced behavioural responses similar to those of psychedelic drugs such as DMT and 5-MeO-DMT, but compounds with larger 7-position substituents such as 7-ethyl-DMT and 7-bromo-DMT did not produce psychedelic-appropriate responding despite high 5-HT2 receptor binding affinity, suggesting these may be antagonists or weak partial agonists for the 5-HT2 receptors. The related compound 7-MeO-MiPT (cf. 5-MeO-MiPT) was also found to be inactive, suggesting that the 7-position has poor tolerance for bulky groups at this position, at least if agonist activity is desired.

<span class="mw-page-title-main">7,N,N-TMT</span> Chemical compound

7,N,N-trimethyltryptamine (7-methyl-DMT, 7-TMT), is a tryptamine derivative which acts as an agonist of 5-HT2 receptors. In animal tests, both 7-TMT and its 5-methoxy derivative 5-MeO-7-TMT produced behavioural responses similar to those of psychedelic drugs such as DMT, but the larger 7-ethyl and 7-bromo derivatives of DMT did not produce psychedelic responses despite having higher 5-HT2 receptor affinity in vitro (cf. DOBU, DOAM). 7-TMT also weakly inhibits reuptake of serotonin but with little effect on dopamine or noradrenaline reuptake.

<span class="mw-page-title-main">2-Bromo-LSD</span> Chemical compound

2-Bromo-LSD, also known as BOL-148 or as bromolysergide, is a derivative of lysergic acid invented by Albert Hofmann, as part of the original research from which the closely related compound LSD was also derived. It is a non-hallucinogenic serotonin 5-HT2A receptor partial agonist, as well as acting at other targets, with psychoplastogenic and antidepressant-like effects in animals.

<span class="mw-page-title-main">Substituted tryptamine</span> Class of indoles

Substituted tryptamines, or simply tryptamines, also known as serotonin analogues (i.e., 5-hydroxytryptamine analogues), are organic compounds which may be thought of as being derived from tryptamine itself. The molecular structures of all tryptamines contain an indole ring, joined to an amino (NH2) group via an ethyl (−CH2–CH2−) sidechain. In substituted tryptamines, the indole ring, sidechain, and/or amino group are modified by substituting another group for one of the hydrogen (H) atoms.

<span class="mw-page-title-main">Tabernanthalog</span> Chemical compound

Tabernanthalog is a novel water-soluble, non-toxic azepinoindole analog of the psychoactive drug Tabernanthine first synthesized by Professor David E. Olson at UC Davis.

<span class="mw-page-title-main">AAZ-A-154</span> Chemical compound

AAZ-A-154, also known as DLX-001 or as (R)-5-methoxy-N,N-dimethyl-α-methylisotryptamine, is a novel isotryptamine derivative which acts as a serotonin 5-HT2A receptor agonist discovered and synthesized by the lab of Professor David E. Olson at the University of California, Davis. It is being developed for the treatment of major depressive disorder and other central nervous system disorders.

Psychoplastogens are a group of small molecule drugs that produce rapid and sustained effects on neuronal structure and function, intended to manifest therapeutic benefit after a single administration. Several existing psychoplastogens have been identified and their therapeutic effects demonstrated; several are presently at various stages of development as medications including ketamine, MDMA, scopolamine, and the serotonergic psychedelics, including LSD, psilocin, DMT, and 5-MeO-DMT. Compounds of this sort are being explored as therapeutics for a variety of brain disorders including depression, addiction, and PTSD. The ability to rapidly promote neuronal changes via mechanisms of neuroplasticity was recently discovered as the common therapeutic activity and mechanism of action.

<span class="mw-page-title-main">6-Fluoro-DET</span> Chemical compound

6-Fluoro-DET is a substituted tryptamine derivative related to drugs such as DET and 5-fluoro-DET. It acts as a partial agonist at the 5-HT2A receptor, but while it produces similar physiological effects to psychedelic drugs, it does not appear to produce psychedelic effects itself even at high doses. For this reason it saw some use as an active placebo in early clinical trials of psychedelic drugs but was regarded as having little use otherwise, though more recent research into compounds such as AL-34662, TBG and AAZ-A-154 has shown that these kind of non-psychedelic 5-HT2A agonists can have various useful applications.

A trip killer, or hallucinogen antidote, is a drug that aborts or reduces the effects of a hallucinogenic drug experience. As there are different types of hallucinogens that work in different ways, there are different types of trip killers. They can completely block or reduce the effects of hallucinogens or they can simply provide anxiety relief and sedation. Examples of trip killers, in the case of serotonergic psychedelics, include serotonin receptor antagonists, like antipsychotics and certain antidepressants, and benzodiazepines. Trip killers are sometimes used by recreational psychedelic users as a form of harm reduction to manage so-called bad trips, for instance difficult experiences with prominent anxiety. They can also be used clinically to manage effects of hallucinogens, like anxiety and psychomotor agitation, for instance in the emergency department.

ITI-1549 is a putatively non-hallucinogenic serotonin 5-HT2A receptor agonist which is under development for the treatment of mood disorders and other psychiatric disorders. In addition to acting at the serotonin 5-HT2A receptor, it is also an antagonist of the serotonin 5-HT2B receptor and an agonist of the serotonin 5-HT2C receptor. The drug's route of administration has not been specified.

<span class="mw-page-title-main">6-MeO-DMT</span> Non-hallucinogenic 5-HT2A agonist

6-MeO-DMT, or 6-methoxy-N,N-dimethyltryptamine, also known as 6-OMe-DMT, is a serotonergic drug of the tryptamine family. It is the 6-methoxy derivative of the serotonergic psychedelic N,N-dimethyltryptamine (DMT) and is a positional isomer of the serotonergic psychedelic 5-MeO-DMT.

BMB-202 is a serotonin 5-HT2A receptor agonist and psychedelic hallucinogen which is under development for the treatment of depressive disorders and post-traumatic stress disorder (PTSD). It is taken by mouth. However, BMB-202 has also been evaluated by injection in preclinical studies.

<span class="mw-page-title-main">Isotryptamine</span> Chemical compound

Isotryptamine, also known as 2-(1-indolyl)ethylamine, is a chemical compound and positional isomer of tryptamine.

<span class="mw-page-title-main">6-MeO-isoDMT</span> Serotonergic psychoplastogen

6-MeO-isoDMT, or 6-OMe-isoDMT, also known as 6-methoxy-N,N-dimethylisotryptamine, is a serotonin 5-HT2A receptor agonist, putative serotonergic psychedelic, and psychoplastogen of the isotryptamine group. It is the isotryptamine analogue of the psychedelic 5-MeO-DMT and is a positional isomer of the non-hallucinogenic psychoplastogen 5-MeO-isoDMT.

<span class="mw-page-title-main">5-MeO-isoDMT</span> Serotonergic psychoplastogen

5-MeO-isoDMT, or 5-OMe-isoDMT, also known as 5-methoxy-N,N-dimethylisotryptamine, is a putatively non-hallucinogenic serotonin 5-HT2A receptor agonist and psychoplastogen of the isotryptamine group. It is the isotryptamine analogue of the non-hallucinogenic 6-MeO-DMT and is a positional isomer of the psychedelic 6-MeO-isoDMT.

α-Methylisotryptamine Monoaminergic drug

α-Methylisotryptamine is a synthetic compound belonging to the tryptamine class, known for its psychoactive properties. As a structural analog of α-methyltryptamine (αMT), isoAMT exhibits entactogenic and psychedelic effects.

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.