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Cited by 95Psychedelics and Drug StudiesSynthesis and bioactivity of alkaloidsAlkaloids: synthesis and pharmacology

Identification of Psychoplastogenic N , N -Dimethylaminoisotryptamine (isoDMT) Analogues through Structure–Activity Relationship Studies

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Dunlap, Lee E., Azinfar, Arya, Ly, Calvin, Cameron, Lindsay P., Viswanathan, Jayashri, Tombari, Robert J., Myers-Turnbull, Douglas, Taylor, Jack C. +4 more·2020·Journal of Medicinal Chemistry
DOI 10.1021/acs.jmedchem.9b01404PMC PMC7075704
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Abstract

Ketamine, N, N -dimethyltryptamine (DMT), and other psychoplastogens possess enormous potential as neurotherapeutics due to their ability to potently promote neuronal growth. Here, we report the first-ever structure–activity relationship study with the explicit goal of identifying novel psychoplastogens. We have discovered several key features of the psychoplastogenic pharmacophore and used this information to develop N, N -dimethylaminoisotryptamine (isoDMT) psychoplastogens that are easier to synthesize, have improved physicochemical properties, and possess reduced hallucinogenic potential as compared to their DMT counterparts.

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Crossref · 10.1021/acs.jmedchem.9b01404

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  • We engineered several non-hallucinogenic analogs of psychedelics with beneficial properties.

    “we were able to engineer several non-hallucinogenic analogs of psychedelics with beneficial properties”

    From Psychedelics and Other Psychoplastogens for Treating Mental Illness. (2021) · cites this paper as [252]

    The Conclusions report that isoDMT derivatives with low hallucinogenic potential promote dendritic growth. In Results and Discussion, compound 5 produced no mouse head-twitch response, but compound 6 was described as less potent than its psychedelic counterpart, not non-hallucinogenic. The paper therefore supports beneficial properties and reduced hallucinogenic potential, but not the claim that several analogs were shown to be non-hallucinogenic. (LLM, conf=0.86)

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Research works printed but not linked: 27

  1. [2]Li N; Lee B; Liu RJ; Banasr M; Dwyer JM; Iwata M; Li XY; Aghaja- nian G; Duman RS mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists. Science 2010, 329, 959– 964. 20724638 PMC3116441
  2. [4]Duman RS; Aghajanian GK; Sanacora G; Krystal JH Synaptic Plasticity and Depression: New Insights from Stress and Rapid-Acting Antidepressants. Nat. Med 2016, 22, 238– 249. 26937618 PMC5405628
  3. [6]Morgan CJ; Curran HV; Independent Scientific Committee on Drugs. Ketamine Use: A Review. Addiction 2012, 107, 27– 38. 21777321
  4. [8]Voleti B; Navarria A; Liu RJ; Banasr M; Li N; Terwilliger R; Sanacora G; Eid T; Aghajanian G; Duman RS Scopolamine Rapidly Increases Mammalian Target of Rapamycin Complex 1 Signaling, Synaptogenesis, and Antidepressant Behavioral Responses. Biol. Psychiatry 2013, 74, 742– 749. 23751205 PMC3773272
  5. [10]Ly C; Greb AC; Cameron LP; Wong JM; Barragan EV; Wilson PC; Burbach KF; Soltanzadeh Zarandi S; Sood A; Paddy MR; Duim WC; Dennis MY; McAllister AK; Ori-McKenney KM; Gray JA; Olson DE Psychedelics Promote Structural and Functional Neural Plasticity. Cell Rep. 2018, 23, 3170– 3182. 29898390 PMC6082376
  6. [12]Cameron LP; Olson DE Dark Classics in Chemical Neuroscience: N,N-Dimethyltryptamine (DMT). ACS Chem. Neurosci 2018, 9, 2344– 2357. 30036036
  7. [13]Cameron LP; Benson CJ; Dunlap LE; Olson DE Effects of N,N-Dimethyltryptamine (DMT) on Rodent Behaviors Relevant to Anxiety and Depression. ACS Chem. Neurosci 2018, 97, 1582– 1590 PMC7196340 29664276
  8. [14]Cameron LP; Benson CJ; DeFelice BC; Fiehn O; Olson DE Chronic, Intermittent Microdoses of the Psychedelic N, N-Dimethyltryptamine (DMT) Produce Positive Effects on Mood and Anxiety in Rodents. ACS Chem. Neurosci 2019, 10, 3261– 3270. 30829033 PMC6639775
  9. [16]Osorŕio FL; Sanches RF; Macedo LR; dos Santos RG; Maia-de-Oliveira JP; Wichert-Ana L; de Araujo DB; Riba J; Crippa JA; Hallak JE Antidepressant Effects of a Single Dose of Ayahuasca in Patients with Recurrent Depression: A Preliminary Report. Rev. Bras. Psiquiatr 2015, 37, 13– 20. 25806551
  10. [18]Speeter ME; Anthony WC The Action of Oxalyl Chloride on Indoles: A New Approach to Tryptamines. J. Am. Chem. Soc 1954, 76, 6208– 6210.
  11. [19]Glennon RA; Jacyno JM; Young R; McKenney JD; Nelson D Synthesis and Evaluation of a Novel Series of N,N-dimethylisotryptamines. J. Med. Chem 1984, 27, 41– 45. 6581313
  12. [20]Chang-Fong J; Addo J; Dukat M; Smith C; Mitchell NA; Herrick-Davis K; Teitler M; Glennon RA Evaluation of Isotryptamine Derivatives at 5-HT(2) Serotonin Receptors. Bio. Org. Med. Chem. Lett 2002, 12, 155– 158. 11755343
  13. [21]Wager TT; Hou X; Verhoest PR; Villalobos A Central Nervous System Multiparameter Optimization Desirability: Application in Drug Discovery. ACS Chem. Neurosci 2016, 6, 767– 775. 26991242
  14. [22]Kurkin AV; Karchava AV; Yurovskaya MA Reaction of 1-(R-Sulfonyl)indoles with N,N-Dibenzyl-β-amino Alcohols. Chem. Heterocycl. Compd 2000, 36, 1141– 1148.
  15. [23]Hill TA; Gordon CP; McGeachie AB; Venn-Brown B; Odell LR; Chau N; Quan A; Mariana A; Sakoff JA; Chircop M; Robinson PJ; McCluskey A Inhibition of Dynamin Mediated Endocytosis by the Dynoles--Synthesis and Functional Activity of a Family of Indoles. J. Med. Chem 2009, 52, 3762– 3773. 19459681
  16. [25]Sundstrom LE Thinking Inside the Box. To Cope with an Increasing Disease Burden, Drug Discovery Needs Biologically Relevant and Predictive Testing Systems. EMBO Rep. 2007, 8, S40– S43. 17726442 PMC3327535
  17. [26]Caceres A; Banker G; Steward O; Binder L; Payne M MAP2 is Localized to the Dendrites of Hippocampal Neurons which Develop in Culture. Brain Res. 1984, 315, 314– 318. 6722593
  18. [27]Ristanovic D; Milosevic NT; Stulic V Application of Modified Sholl Analysis to Neuronal Dendritic Arborization of the Cat Spinal Cord. J. Neurosci. Methods 2006, 158, 212– 218. 16814868
  19. [28]Lima da Cruz RA; Moulin TC; Petiz LL; Leão R, A N Single Dose of 5-MeO-DMT Stimulates Cell Proliferation, Neuronal Survivability, Morphological and Functional Changes in Adult Mice Ventral Dentate Gyrus. Front. Mol. Neurosci 2018, 11, 312. 30233313 PMC6131656
  20. [32]Glennon RA; Young R. l; Jacyno JM; Slusher M; Rosecrans JA DOM-Stimulus Generalization to LSD and other Hallucinogenic Indolealkylamines. Eur. J. Pharmacol 1983, 86, 453– 459. 6572591
  21. [33]Meanwell NA Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design. J. Med. Chem 2018, 61, 5822– 5880. 29400967
  22. [34]Wacker D; Wang S; McCorvy JD; Betz RM; Venkatakrishnan AJ; Levit A; Lansu K; Schools ZL; Che T; Nichols DE; Shoichet BK; Dror RO; Roth BL Crystal Structure of an LSD-Bound Human Serotonin Receptor. Cell 2017, 168, 377– 389. 28129538 PMC5289311
  23. [35]McCarroll M; Gendelev L; Kinser R; Taylor J; Bruni G; Myers-Turnbull D; Helsell C; Carbajal A; Rinaldi C; Kang HJ; Gong JH; Sello J; Tomita S; Peterson R; Keiser M; Kokel D Zebrafish Behavioural Profiling Identifies GABA and Serotonin Receptor Ligands Related to Sedation and Paradoxical Excitation. Nat. Comm, 2019, 10, 4078. PMC6733874 31501447
  24. [36]Hanks JB; González-Maeso J Animal Models of Serotonergic Psychedelics. ACS Chem. Neurosci, 2013, 4, 33– 42. 23336043 PMC3547517
  25. [37]Tombari RJ; Saunders CM; Wu CY; Dunlap LE; Tantillo DJ; Olson DE Ex Vivo Analysis of Tryptophan Metabolism Using 19F NMR, ACS Chem. Biol, 2019, 14, 1866– 1873. 31449387 PMC7075705
  26. [38]Buemi MR; De Luca L; Chimirri A; Ferro S; Gitto R; Alvarez-Builla J; Alajarin R Indole Derivatives as Dual-Effective Agents for the Treatment of Neurodegenerative Diseases: Synthesis, Biological Evaluation, and Molecular Modeling Studies. Bioorg. Med. Chem 2013, 21, 4575– 4580. 23777828
  27. [39]Westerfield Monte. The Zebrafish Book: A Guide for the Laboratory Use of Zebrafish (Danio Rerio). University of Oregon Press 2000.

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Authors
Dunlap, L. E., Azinfar, A., Ly, C., Cameron, L. P., Viswanathan, J., Tombari, R. J., Myers-Turnbull, D., Taylor, J. C., Grodzki, A. C., Lein, P. J., Kokel, D., & Olson, D. E.
Affiliations
  • University of California, Davis (US)
  • University of California, San Francisco (US)
Corresponding author
Olson, David E.
ORCID
Venue
Journal of Medicinal Chemistry
Publisher
American Chemical Society (ACS)
Published
2020-01-24
Volume
63
Issue
3
Pages
1142-1155
ISSN
  • 0022-2623 (ISSN-L)
  • 1520-4804
DOI
10.1021/acs.jmedchem.9b01404
PMC
PMC7075704
OpenAlex
W3002940062
Cited by
95
References
12
Citations by year
2026: 11 · 2025: 22 · 2024: 17 · 2023: 14 · 2022: 11 · 2021: 8 · 2020: 10 · 2019: 2
FWCI
4.30
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Medicinal Chemistry (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • University of California, Davis
  • National Institute of Child Health and Human Development (U54 HD079125)
  • Paul G. Allen Family Foundation
  • National Institute on Alcohol Abuse and Alcoholism (R01AA022583)
  • Genentech Foundation
  • Hellman Foundation
  • National Institute of General Medical Sciences (R01GM128997)
Topics
  • Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Synthesis and bioactivity of alkaloids
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Alkaloids: synthesis and pharmacology
Keywords
psychoplastogens, structure-activity relationship, pharmacophore, neuronal growth, neurotherapeutics, DMT, ketamine, tryptamine derivatives
MeSH terms
Animals, N,N-Dimethyltryptamine, Hallucinogens, Neuronal Plasticity, Neurons, Structure-Activity Relationship, Zebrafish, Molecular Structure, Mice

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