Dimethylhomotryptamine

Last updated

Dimethylhomotryptamine
Dimethylhomotryptamine.svg
Clinical data
Other namesDMHT; U-6056; U6056; N,N-Dimethylhomotryptamine; 3-[3-(Dimethylamino)propyl]indole
Drug class Serotonin receptor modulator
ATC code
  • None
Identifiers
  • 3-(1H-indol-3-yl)-N,N-dimethylpropan-1-amine
CAS Number
PubChem CID
ChemSpider
ChEMBL
Chemical and physical data
Formula C13H18N2
Molar mass 202.301 g·mol−1
3D model (JSmol)
  • CN(C)CCCC1=CNC2=CC=CC=C21
  • InChI=1S/C13H18N2/c1-15(2)9-5-6-11-10-14-13-8-4-3-7-12(11)13/h3-4,7-8,10,14H,5-6,9H2,1-2H3
  • Key:QHNWPRMHGXRBAO-UHFFFAOYSA-N

Dimethylhomotryptamine (DMHT; developmental code name U-6056), also known as N,N-dimethylhomotryptamine or as 3-[3-(dimethylamino)propyl]indole, is a homotryptamine and homologue of the psychedelic tryptamine dimethyltryptamine (DMT) in which the alkyl side chain has been lengthened by one carbon atom. [1] [2] [3] [4] [5] The homologue of DMT in which the alkyl side chain has been shortened by one carbon atom is gramine (3-(N,N-dimethylaminomethyl)indole). [1]

Contents

According to Alexander Shulgin in his book TiHKAL (Tryptamines I Have Known and Loved) and other publications, DMHT was studied by the Upjohn Company under the code name U-6056. [1] [2] [5] It was assessed in a clinical study of 10 individuals at doses of up to 10 mg by intravenous injection and 70 mg by intramuscular injection, but produced no psychoactive or hallucinogenic effects besides mild agitation or anxiety and caused slight increases in heart rate and blood pressure. [1] [2] [3] [4] [5] For comparison, DMT has been reported to produce psychedelic effects at doses as low as 20 to 50 mg by intramuscular injection. [1] The human properties and effects of the lower homologue gramine are unknown. [1]

DMHT showed the same affinity for serotonin receptors in the rat fundus strip as DMT (A2 = 1,000 nM and 1,000 nM, respectively). [6] [7] It also shows low affinity for the serotonin 5-HT3 receptor (Ki = 730 nM). [8] The drug's analogue homotryptamine (the N,N-didesmethyl analogue) showed abolished affinity for the serotonin 5-HT1E and 5-HT1F receptors (Ki = >10,000 nM). [9] DMHT is a potent serotonin reuptake inhibitor (SRI), with an affinity (IC50 Tooltip half-maximal inhibitory concentration) for the serotonin transporter (SERT) of 58 nM. [10] It produced hyperthermia in rabbits. [4] [11] [12] [13]

The chemical synthesis of DMHT has been described. [6] Other DMT and DMHT homologues with further extended alkyl chains have been studied, but were said to have no interesting activity. [4] [13] The highly potent selective serotonin reuptake inhibitor (SSRI) BMS-505130 (Ki = 0.18 nM for the SERT) was derived via structural modification of DMHT. [14] [15]

DMHT was first described in the scientific literature by William J. Turner and Sidney Merlis in 1959. [5]

See also

References

  1. 1 2 3 4 5 6 Shulgin, Alexander; Shulgin, Ann (September 1997). TiHKAL: The Continuation. Berkeley, California: Transform Press. ISBN   0-9630096-9-9. OCLC   38503252. "How can something that is not orally active be orally active? A possible explanation is the presence of another indole with a one-carbon shorter chain. This is gramine, or 3-(N,N-dimethylaminomethyl)indole which is synthesized in the plant with an entirely different set of enzymes. Its human pharmacology is not known. A related homologue, one carbon longer, is the three-carbon chain compound 3-[3-(dimethylamino)propyl]indole, produced by the Upjohn Company. It has been studied clinically under the code name U-6056, at levels of up to 70 milligrams in 10 subjects, by i.m. injection. There were no reports of visual, auditory or tactile disturbances. Physically, there was a slight increase in blood pressure anad pulse rate. Certainly there were no psychological effects."
  2. 1 2 3 Shulgin AT (1976). "Psychotomimetic Agents". In Gordon M (ed.). Psychopharmacological Agents: Use, Misuse and Abuse. Medicinal Chemistry: A Series of Monographs. Vol. 4. Academic Press. pp. 59–146. doi:10.1016/b978-0-12-290559-9.50011-9. ISBN   978-0-12-290559-9. Turner and Merlis (1959) have found only vague restlessness at [DMT] levels of 25 mg im and give the lowest effective dose in man as 50 mg. Orally, even 350 mg was without effect. [...] One additional homologous system has been evaluated in man. This is the three-carbon chain homolog (XXVI) of N,N-dimethyltryptamine. This compound, intramuscularly administered to normal subjects at levels of up to 80 mg, gave no central stimulation (Turner and Merlis, 1959).
  3. 1 2 Shulgin AT (1980). "Hallucinogens". In Burger A, Wolf ME (eds.). Burger's Medicinal Chemistry. Vol. 3 (4 ed.). New York: Wiley. pp. 1109–1137. ISBN   978-0-471-01572-7. OCLC   219960627. The lengthening of the side chain of DMT to three carbon atoms results in 60.32, which was without central effects following parenteral administration of 80 mg (33).
  4. 1 2 3 4 Nichols DE, Glennon RA (1984). "Medicinal Chemistry and Structure-Activity Relationships of Hallucinogens". In Jacobs BL (ed.). Hallucinogens: Neurochemical, Behavioral, and Clinical Perspectives. New York: Raven Press. pp. 95–142. ISBN   978-0-89004-990-7. OCLC   10324237. Lengthening of the side chain of DMT by a single methylene group produces N,N-dimethylhomotryptamine (DMHT; 76, R = H, n = 3). which produced hyperthermia when administered to rabbits (7,232) but was found to be inactive in man (235). Intravenous administration of 5 and 10 mg and intramuscular injection of 20 to 70 mg DMHT was without psychologic effect in 10 human subjects (235). Additional studies on DMHT homologs (i.e., 76, n = 4–10) did not show any interesting activity (7,232).
  5. 1 2 3 4 Turner WJ, Merlis S (January 1959). "Effect of some indolealkylamines on man". AMA Arch Neurol Psychiatry. 81 (1): 121–129. doi:10.1001/archneurpsyc.1959.02340130141020. PMID   13605329.
  6. 1 2 Glennon RA, Gessner PK (April 1979). "Serotonin receptor binding affinities of tryptamine analogues". J Med Chem. 22 (4): 428–432. doi:10.1021/jm00190a014. PMID   430481. Comparing DMT with compounds 18 and 16, it appears that extending the side chain by one methylene unit or replacing the indole nitrogen by a sulfur atom has no effect on affinity. [...] As revealed in Table I, increasing the chain length of DMT (1) by one methylene unit to DMHT (18) has no effect on affinity. Perhaps by varying the conformation of the propylamine side chain, the terminal amine function of DMHT (18) can approximate that distance from the indole ring which is usually achieved by the terminal amine of DMT (1).
  7. ↑ Van Vunakis H, Farrow JT, Gjika HB, Levine L (July 1971). "Specificity of the antibody receptor site to D-lysergamide: model of a physiological receptor for lysergic acid diethylamide". Proc Natl Acad Sci U S A. 68 (7): 1483–1487. doi:10.1073/pnas.68.7.1483. PMC   389223 . PMID   5283939.
  8. ↑ Glennon, R. A.; Peroutka, S. J.; Dukat, M. (1991). "Binding Characteristics of a Quaternary Amine Analog of Serotonin: 5-HTQ". Serotonin: Molecular Biology, Receptors and Functional Effects. Basel: Birkhäuser Basel. p. 186–191. doi:10.1007/978-3-0348-7259-1_17. ISBN   978-3-0348-7261-4 . Retrieved 11 November 2025. Because the possibility exists that 5-HT3 receptors may accommodate ligands with a greater ring-to-amine distance than that found in 5-HT, we examined two "extended" tryptamine analogs, or tryptamine analogs where an additional methylene group has been inserted in the alkyl side chain: homotryptamine [i.e., 3-(3-amino-n-propyl)indole] and N,N-dimethylhomotryptamine. Homotryptamine binds at 5-HT3 receptors with low affinity (Ki > 2,000 nM). N,N-Dimethylhomotryptamine also binds with low affinity (Ki = 730 nM) but reveals that the two terminal amine methyl groups contribute to binding. Additional studies with these types of agents are in progress.
  9. ↑ Klein MT, Dukat M, Glennon RA, Teitler M (June 2011). "Toward selective drug development for the human 5-hydroxytryptamine 1E receptor: a comparison of 5-hydroxytryptamine 1E and 1F receptor structure-affinity relationships". J Pharmacol Exp Ther. 337 (3): 860–867. doi:10.1124/jpet.111.179606. PMC   3101003 . PMID   21422162.
  10. ↑ Schmitz WD, Denhart DJ, Brenner AB, Ditta JL, Mattson RJ, Mattson GK, Molski TF, Macor JE (March 2005). "Homotryptamines as potent and selective serotonin reuptake inhibitors (SSRIs)". Bioorg Med Chem Lett. 15 (6): 1619–1621. doi:10.1016/j.bmcl.2005.01.059. PMID   15745809. Table 1. SERT binding affinitiesa of homotryptamines [...] Compound: 2B [...]
  11. ↑ Glennon RA, Rosecrans JA (1982). "Indolealkylamine and phenalkylamine hallucinogens: a brief overview". Neurosci Biobehav Rev. 6 (4): 489–497. doi:10.1016/0149-7634(82)90030-6. PMID   6757811. Animal data are also available on a number of other related compounds such as 4,5,6-trimethoxy and 5,6,7-trimethoxy DMT, 5-OMe-6-OH DMT and dimethylhomotryptamine [52, 70, 71, 74], but human data are unavailable.
  12. ↑ Trubitsyna TK, Mashkovskiĭ MD (1970). "Farmakologicheskie svoĭstva nekotorykh gomologov triptamina" [Pharmacological properties of some tryptamine homologues]. Farmakol Toksikol (in Russian). 33 (4): 387–392. PMID   5525947.
  13. 1 2 Fedorova, V. S., Orlova, I. A., & Trubitsyna, T. K. (1970). The synthesis and pharmacological properties of tryptamine homologs. Khim. Farm. Zh, 4, 10–14.
  14. ↑ Yao, Chuansheng; Jiang, Xiaoying; Ye, Xiang‐Yang; Xie, Tian; Bai, Renren (2022). "Antidepressant Drug Discovery and Development: Mechanism and Drug Design Based on Small Molecules". Advanced Therapeutics. 5 (5). doi:10.1002/adtp.202200007. ISSN   2366-3987 . Retrieved 11 November 2025.
  15. ↑ Mattson RJ, Catt JD, Denhart DJ, Deskus JA, Ditta JL, Higgins MA, Marcin LR, Sloan CP, Beno BR, Gao Q, Cunningham MA, Mattson GK, Molski TF, Taber MT, Lodge NJ (September 2005). "Conformationally restricted homotryptamines. 2. Indole cyclopropylmethylamines as selective serotonin reuptake inhibitors". J Med Chem. 48 (19): 6023–6034. doi:10.1021/jm0503291. PMID   16162005.
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