N-DEAOP-NMT

Last updated

N-DEAOP-NMT
N-DEAOP-NMT.svg
Clinical data
Other namesN-(3-Diethylamino-3-oxopropyl)-NMT; N-DEAOP-NMT; N-(2-Diethylcarbamoylethyl)-N-methyltryptamine; N-DECE-NMT; NMT-N-(CH2-CH2-CONEt2)
Drug class Simplified/non-rigid LSD analogue
Chemical and physical data
Formula C18H27N3O
Molar mass 301.434 g·mol−1
3D model (JSmol)
  • CCN(CC)C(=O)CCN(C)CCc1c[nH]c2ccccc12
  • InChI=1S/C18H27N3O/c1-4-21(5-2)18(22)11-13-20(3)12-10-15-14-19-17-9-7-6-8-16(15)17/h6-9,14,19H,4-5,10-13H2,1-3H3
  • Key:KRNAXWYCPYUSGZ-UHFFFAOYSA-N

N-(3-Diethylamino-3-oxopropyl)-N-methyltryptamine (N-DEAOP-NMT) is a tryptamine derivative and a "partial" or "simplified" ergoline which is closely related to the extremely potent serotonergic psychedelic lysergic acid diethylamide (LSD). [1] [2] [3] [4] It is the analogue of LSD in which two of LSD's carbon atoms in the ergoline ring, carbons 9 and 10, have been removed. [1] [2] [3] [4] This in turn renders the N-DEAOP-NMT molecule flexible and makes it a non-rigid tryptamine rather than an ergoline. [1] [2] [3] [4] The compound is pharmacologically active, as are a number of its analogues and derivatives, with activities of the compounds including serotonin 5-HT2A receptor agonism and LSD- or hallucinogen-like effects. [1] [2] [3] [4]

Contents

LSD (left) and N-DEAOP-NMT (right) chemical structures. LSD and N-DEAOP-NMT chemical structures.png
LSD (left) and N-DEAOP-NMT (right) chemical structures.

Pharmacology

N-DEAOP-NMT has been found to produce quantifiable oxytocic effects in animals. [1] [4] However, in contrast to other lysergamides such as lysergic acid and ergonovine, N-DEAOP-NMT was said to not possess significant oxytocic activity relative to clinically used oxytocic drugs, and hence to have little such activity. [1] [4] On the other hand, it was noted to possess 10-fold greater oxytocic activity than that of N-(3-diethylamino-3-oxopropyl)-N-methylphenethylamine (N-DEAOP-NMPEA), a phenethylamine-based simplified and non-rigid LSD analogue that was also evaluated in the study. [4]

Analogues and derivatives

N-DEAOP-NET

The N-ethyl variant of N-DEAOP-NMT, as opposed to N-DEAOP-NMT itself (which is the N-methyl form), is N-(3-diethylamino-3-oxopropyl)-N-ethyl-5-tryptamine (N-DEAOP-NET), and has been described. [1] [3] This compound is a simplified and non-rigid analogue of ETH-LAD rather than of LSD (which is also known as "METH-LAD"). [1] [3] In contrast to N-DEAOP-NMT, N-DEAOP-NET has been evaluated specifically for LSD- or hallucinogen-like effects in animals. [1] [3] LSD produced a typical behavioral and physiological syndrome at an effective-to-fatal dose range of 0.1–5.0 mg/kg in rats, whereas the range for N-DEAOP-NET was 1.0–10.0 mg/kg. [1] [3] The effects of N-DEAOP-NET were qualitatively similar to those of LSD, and included strong mydriasis, hyperreflexia, tremors, hypothermia, hyperactivity, skin hyperemia, stereotypy, fearful reactions, and disorientation, among others. [1] [3] Based on the preceding findings, it has been concluded that N-DEAOP-NET shows LSD-like effects and hence may produce psychedelic effects in humans but is about 10 times less potent than LSD at least in rodents. [1] [3] Various other analogues were also assessed and described. [3]

5-MeO-N-DEAOP-NMT

The 5-methoxy analogue of N-DEAOP-NMT, N-(3-diethylamino-3-oxopropyl)-N-methyl-5-methoxytryptamine (5-MeO-N-DEAOP-NMT), also known as N-(2-diethylcarbamoylethyl)-N-methyl-5-methoxytryptamine (5-MeO-N-DECE-NMT), has been described. [2] Its affinities (Ki) for serotonin receptors were 21 nM for the serotonin 5-HT1A receptor, 697 nM for the serotonin 5-HT2A receptor, and 1,184 nM for the serotonin 5-HT2C receptor. [2] For comparison, the serotonergic psychedelic dimethyltryptamine (DMT) had affinities for these receptors of 38 nM, 1,093 nM, and 211 nM, respectively, while the psychedelic 5-MeO-DMT had affinities of 4.2 nM, 558 nM, and 187 nM, respectively. [2] 5-MeO-N-DEAOP-NMT was a partial agonist of the serotonin 5-HT2A receptor, with an EC50 Tooltip half-maximal effective concentration of 2,338 nM and an Emax Tooltip maximal efficacy of 16–40%, whereas DMT was a partial agonist with an EC50 of 2,239 nM and an Emax of 16–41% while 5-MeO-DMT was a partial to full agonist with an EC50 of 741 nM and an Emax of 57–98%. [2] Hence, 5-MeO-N-DEAOP-NMT showed fairly similar affinities for serotonin receptors and activational potencies and efficacies at the serotonin 5-HT2A receptor compared to the well-known DMT. [2] N-DEAOP-NMT was also included in the study, but its values were not reported. [2]

5-MeO-N-DEAOP-NET

5-MeO-N-DEAOP-NET, or N-(3-diethylamino-3-oxopropyl)-N-ethyl-5-methoxytryptamine, the 5-methoxy analogue of N-DEAOP-NET, was also notably evaluated in the previously discussed animal study of LSD-like effects with N-DEAOP-NE and other analogues, but it was not as potent as N-DEAOP-NET and its dose range was not reported. [3]

Others

Other simplified non-rigid LSD analogues, like CT-5252 and NDTDI among others, have additionally been synthesized and assayed. [1] [2] [3] [4] [5] [6]

History

N-DEAOP-NMT was first described in the scientific literature by 1952. [1] [4] This followed the synthesis of LSD by chemist Albert Hofmann in 1938 and the discovery of LSD's psychedelic effects by Hofmann in 1943. [7] N-DEAOP-NMT and other simplified non-rigid LSD analogues were notably reviewed and discussed by psychedelic chemist David E. Nichols in his Ph.D. thesis on LSD analogues and other psychedelic compounds in 1973. [1] N-DEAOP-NMT's derivatives N-DEAOP-NET and 5-MeO-N-DEAOP-NET, as well as LSD- or hallucinogen-like effects of these compounds, was first described in the literature by 1971, [1] [3] while 5-MeO-N-DEAOP-NMT and its serotonin receptor interactions were first described by 2005. [2]

See also

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Nichols DE (May 1973). Potential Psychotomimetics: Bromomethoxyamphetamines and Structural Congeners of Lysergic Acid (Thesis). University of Iowa. pp. 23–23. OCLC   1194694085. Sklar, et al. (53) found the diethylacrylamide adduct 20 to be approximately 1/10 as active as LSD in mice, although Norris and Blicke (54) reported 21 to have little oxytocic activity. [...] 20 = R = C2H5. 21 = R = CH3 [...] [...] Julia, Igolen and Kolb (50) have prepared 16 and 17 as analogs of lysergic acid but no biological activities have been reported. [...] 50. M. Julia, J. Igolen, and A. Kolb, C. R. Acad. Sci., Paris, Ser. C, 273, 1776 (1971). [...] 53. S. Sklar, K. A. Nieforth, and M. Malone, J. Pharm. Sci., 60, 304 (1971). 54. P. E. Norris and F. F. Blicke, J. Amer. Pharm. Ass. (Scientific ed.), XLI, 637 (1952).
  2. 1 2 3 4 5 6 7 8 9 10 11 12 Jensen N (2005). Tryptamines as Ligands and Modulators of the Serotonin 5‑HT2A Receptor and the Isolation of Aeruginascin from the Hallucinogenic Mushroom Inocybe aeruginascens (Ph.D. thesis). Georg-August-University Göttingen. pp. 71, 178–179, 216, 254, 258, 262, 266, 270, 274, 278, 282, 286. doi: 10.53846/goediss-2111 . Retrieved 19 March 2025. Binding Data for the 5-HT1A receptor [...] Introduction of a carbonyl functionality into the substituent had a detrimental effect on affinity for all tested compounds if compared to the methyl substituent as well as compared to straight alkyl groups of comparable length. [...] Binding affinities of straight chain alkyl compounds at the 5-HT2A receptor [...] As seen for the 5-HT1A receptor, adding carbonyl functionalities to the side chain had strongly detrimental effects on binding affinity. Especially the more hydrophilic CH2-CONH2 substituted compounds 231 and 232 showed negligible binding affinity. Only the longer and more lipophilic (CH2-CH2-CONEt2)-5-MeO-DMT (302) had similar affinity to 5-MeO-NMT (208) and 5-MeO-DMT (15). [...] N-(Carbamoylmethyl)-N-methyltryptamine hydrogen oxalate (2-{[2-(Indol-3-yl)-ethyl]-methylamino}-acetamide hydrogen oxalate) (231) [...] N-(Carbamoylmethyl)-N-methyl-5-methoxytryptamine hydrogen oxalate (2-{[2-(5-Methoxyindol-3-yl)-ethyl]-methylamino}-acetamide hydrogen oxalate) (232) [...] N-(2-Diethylcarbamoylethyl)-N-methyltryptamine hydrogen oxalate (N,N-Diethyl-3-{[2-(indol-3-yl)-ethyl]-methylamino}-propionamide hydrogen oxalate) (301) N-(2-Diethylcarbamoylethyl)-N-methyltryptamine hydrogen oxalate (C18H27N3O⋅C2H2O4, 391.46 g/mol) was obtained as a non-crystallizing oily precipitate from 115.2 mg 3-bromo-N,N-diethylpropionamide (183, 208.1 g/mol, 100%, 553.6 µmol) and 85.3 mg N-methyltryptamine (211, 174.24 g/mol, 489.5 µmol) by general procedure E. N-(2-Diethylcarbamoylethyl)-N-methyl-5-methoxytryptamine hydrogen oxalate (N,N-Diethyl-3-{[2-(5-methoxyindol-3-yl)-ethyl]-methylamino}-propionamide hydrogen oxalate) (302) [...]
  3. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Sklar S, Nieforth KA, Malone M (February 1971). "Synthesis and preliminary screening of N-ethyltryptamine derivatives related to reserpine and lysergic acid". J Pharm Sci. 60 (2): 304–306. doi:10.1002/jps.2600600235. PMID   5572462. Fourteen derivatives of N-ethyltryptamine, structurally related to [...] lysergic acid, were synthesized. These compounds [...] were screened for gross pharmacologic activity in unanesthetized rats. [...] LSD-like activity was found in those compounds most closely related to lysergic acid. [...] Fourteen amides and esters of N-ethyl-N-(3-indolylethyl)-ω-aminoalkyl carboxylic acid were synthesized. [...] Psychotomimetic activity would be anticipated in those compounds that had a two-carbon chain separating the tryptamine and carbonyl function as in lysergic acid diethylamide. [...] The characteristic symptomatology produced by d-lysergic acid diethylamide tartrate (0.1-5.0 mg./kg.) is manifested as a rapid onset of profound mydriasis, pilomotor erection, and hypothermia associated with spontaneous statue positions and stereotypy at doses that do not affect the animal's motor performance significantly. At doses of 1.0-5.0 mg./kg., hyperactivity, hyperreflexia, and tremors are apparent as well as fearful-aggressive reaction patterns to body grasp and head tap challenges. Death following a dosage of 5.0 mg./kg. occurs within 30-45 min. and is associated with cardiac irregularities and general rigidity of musculature, [...] the diethylamino derivatives appeared to possess some qualitatively similar lysergic acid-like activity, with Compound XVI [(N-DEAOP-NET)] being the most potent, [...] Compound XVI, in the equivocally effective-to-lethal dosage range of 1.0-10.0 mg./kg., produced dose-response patterns of strong mydriasis, hyperreflexia, tremors, hypothermia, increased motor activity, hyperemia of skin, and evidences for stereotypy and disorientation. Fearful reaction patterns to the head tap and body grasp challenges were observed uniformly. [...] Each amide showed various degrees of LSD-like activity. The molecule derived directly from the disjuncture of LSD, that is, the diethylamide of the compound where the alkyl chain possesses two carbons, was quantitatively the most potent, showing the desired activity at levels of 1.0-10.0 mg./kg. As the alkyl chain was lengthened, potency decreased. The dimethyl amides were active but to a lesser degree.
  4. 1 2 3 4 5 6 7 8 9 Norris PE, Blicke FF (December 1952). "Potential ergot substitutes: esters and amides of beta-amino acids". J Am Pharm Assoc Am Pharm Assoc. 41 (12): 637–639. doi:10.1002/jps.3030411204. PMID   13022416. Six esters and amides of derivatives of β-alanine which are related to lysergic acid have been prepared and tested for oxytocic activity. None of these products possess a significant oxytocic activity. [...] The purpose of this investigation was to synthesize amides and also esters of compounds (II–V) which represent fragments of the lysergic acid molecule in the hope that some of these products might possess oxytocic activity. Various modified fragments of the lysergic acid molecule have been synthesized previously; it was claimed that some of the compounds are active oxytocics (1—7). [...] Pharmacologic data indicated that none of the esters or amides of compounds II—V which were prepared possess a significant oxytocic action when compared to the clinically used oxytocics. However, the diethylamide of N-methyl-N-[β′-(3-indolyl)-ethyl]-β-alanine (IIIc) appeared to have an oxytocic activity approximately ten times stronger than that of the diethylamide of N-methyl-N-(β′-phenethyl)-β-alanine (IIc).
  5. ↑ Julia M, Igolen J, Kolb A (20 December 1971). "Preparation de quelques phenyl et indolyl-5-tetrahydro-1.2.3.6 nicotinamides" [Preparation of some phenyl and indol-5-yl-1,2,3,6-tetrahydronicotinamides]. Comptes rendus hebdomadaires des séances de l'Académie des sciences. Série C. 273 (25): 1776–1777. Archived from the original on 2 February 2021.
  6. ↑ Sivadjian J (May 1970). "Etude psychopharmacologique de quelques dérivés analogues à l'acide lysergique" [Psychopharmacological study of some derivatives analogous with lysergic acid]. C R Acad Hebd Seances Acad Sci D (in French). 270 (20): 2499–2501. PMID   4987582.
  7. ↑ A. Hofmann (15 August 1994). "History of the discovery of LSD". In Pletscher A, Ladewig D (eds.). 50 Years of LSD: Current Status and Perspectives of Hallucinogens. A Symposium of the Swiss Academy of Medical Sciences, Lugano-Agno (Switzerland), October 21 and 22, 1993. New York: Parthenon Publishing Group. pp. 7–16. ISBN   9781850705697. OCLC   30034178. OL   1084474M. Time and again I hear or read that LSD was an accidental discovery, that LSD was discovered by chance. This is only partly true. LSD was already 5 years old when chance came into play. I had prepared this compound in 1938 in the course of planned research, but it was only in 1943 that I discovered, by chance, its extra- ordinary psychical effects. I had planned to prepare an analeptic, a circulatory stimulant, but then found a psychical stimulant of unprecedented potency. The English vocabulary has a term for such discoveries — 'serendipity' — meaning a kind of planned accident, or planned chance.


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