Chemistry:Dimethylhomotryptamine

From HandWiki

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]

Use and effects

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]

Pharmacology

Pharmacodynamics

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) for the serotonin transporter (SERT) of 58 nM.[10] It produced hyperthermia in rabbits.[4][11][12][13]

Chemistry

Synthesis

The chemical synthesis of DMHT has been described.[6]

Analogues

File:Homotryptamine structure.svg
Homotryptamine.

DMHT's N,N-didesmethyl analogue is homotryptamine.[9] Other DMT and DMHT homologues with further extended alkyl side 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] Gramine is an analogue of DMT and DMHT with a shortened alkyl side chain.[1]

History

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

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Shulgin, Alexander; Shulgin, Ann (September 1997). TiHKAL: The Continuation. Berkeley, California: Transform Press. ISBN 0-9630096-9-9. OCLC 38503252. http://www.erowid.org/library/books_online/tihkal/tihkal.shtml.  "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. ↑ 2.0 2.1 2.2 "Psychotomimetic Agents". Psychopharmacological Agents: Use, Misuse and Abuse. Medicinal Chemistry: A Series of Monographs. 4. Academic Press. 1976. pp. 59–146. doi:10.1016/b978-0-12-290559-9.50011-9. ISBN 978-0-12-290559-9. https://bitnest.netfirms.com/external/10.1016/B978-0-12-290559-9.50011-9. "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. ↑ 3.0 3.1 "Hallucinogens". Burger's Medicinal Chemistry. 3 (4 ed.). New York: Wiley. 1980. pp. 1109–1137. ISBN 978-0-471-01572-7. OCLC 219960627. https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=6ac0c892ee380436f614d3aae0686ef617b2e0c5. "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. ↑ 4.0 4.1 4.2 4.3 "Medicinal Chemistry and Structure-Activity Relationships of Hallucinogens". Hallucinogens: Neurochemical, Behavioral, and Clinical Perspectives. New York: Raven Press. 1984. pp. 95–142. ISBN 978-0-89004-990-7. OCLC 10324237. https://bitnest.netfirms.com/external/Books/HallucinogensNBCP95. "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. ↑ 5.0 5.1 5.2 5.3 "Effect of some indolealkylamines on man". A.M.A. Archives of Neurology and Psychiatry 81 (1): 121–129. January 1959. doi:10.1001/archneurpsyc.1959.02340130141020. PMID 13605329. 
  6. ↑ 6.0 6.1 "Serotonin receptor binding affinities of tryptamine analogues". Journal of Medicinal Chemistry 22 (4): 428–432. April 1979. 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. ↑ "Specificity of the antibody receptor site to D-lysergamide: model of a physiological receptor for lysergic acid diethylamide". Proceedings of the National Academy of Sciences of the United States of America 68 (7): 1483–1487. July 1971. doi:10.1073/pnas.68.7.1483. PMID 5283939. 
  8. ↑ "Binding Characteristics of a Quaternary Amine Analog of Serotonin: 5-HTQ". Serotonin: Molecular Biology, Receptors and Functional Effects. Basel: Birkhäuser Basel. 1991. pp. 186–191. doi:10.1007/978-3-0348-7259-1_17. ISBN 978-3-0348-7261-4. http://link.springer.com/10.1007/978-3-0348-7259-1_17. 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. ↑ 9.0 9.1 "Toward selective drug development for the human 5-hydroxytryptamine 1E receptor: a comparison of 5-hydroxytryptamine 1E and 1F receptor structure-affinity relationships". The Journal of Pharmacology and Experimental Therapeutics 337 (3): 860–867. June 2011. doi:10.1124/jpet.111.179606. PMID 21422162. 
  10. ↑ "Homotryptamines as potent and selective serotonin reuptake inhibitors (SSRIs)". Bioorganic & Medicinal Chemistry Letters 15 (6): 1619–1621. March 2005. doi:10.1016/j.bmcl.2005.01.059. PMID 15745809. "Table 1. SERT binding affinitiesa of homotryptamines [...] Compound: 2B [...]". 
  11. ↑ "Indolealkylamine and phenalkylamine hallucinogens: a brief overview". Neuroscience and Biobehavioral Reviews 6 (4): 489–497. 1982. 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. ↑ "[Pharmacological properties of some tryptamine homologues]" (in Russian). Farmakologiia I Toksikologiia 33 (4): 387–392. 1970. PMID 5525947. 
  13. ↑ 13.0 13.1 "The synthesis and pharmacological properties of tryptamine homologs.". Khimiko-Farmatsevticheskii Zhurnal 4: 10–14. 1970. 
  14. ↑ "Antidepressant Drug Discovery and Development: Mechanism and Drug Design Based on Small Molecules". Advanced Therapeutics 5 (5). 2022. doi:10.1002/adtp.202200007. ISSN 2366-3987. https://advanced.onlinelibrary.wiley.com/doi/10.1002/adtp.202200007. Retrieved 11 November 2025. 
  15. ↑ "Conformationally restricted homotryptamines. 2. Indole cyclopropylmethylamines as selective serotonin reuptake inhibitors". Journal of Medicinal Chemistry 48 (19): 6023–6034. September 2005. doi:10.1021/jm0503291. PMID 16162005. 



Retrieved from "https://handwiki.org/wiki/index.php?title=Chemistry:Dimethylhomotryptamine&oldid=4310156"