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O-Acetylbufotenine

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O-Acetylbufotenine
Clinical data
Other namesO-Acetylbufotenin; Bufotenine acetate; Bufotenin acetate; Bufotenine O-acetate; Bufotenin O-acetate; 5-Acetoxy-N,N-dimethyltryptamine; 5-Acetoxy-DMT; 5-AcO-DMT; 5-Acetoxy-N,N-DMT; O-Acetyl-N,N-dimethylserotonin
Drug classSerotonin receptor agonist; Serotonergic psychedelic
Identifiers
  • [3-[2-(dimethylamino)ethyl]-1H-indol-5-yl] acetate
CAS Number
PubChem CID
ChemSpider
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC14H18N2O2
Molar mass246.310 g·mol−1
3D model (JSmol)
  • CC(=O)OC1=CC2=C(C=C1)NC=C2CCN(C)C
  • InChI=1S/C14H18N2O2/c1-10(17)18-12-4-5-14-13(8-12)11(9-15-14)6-7-16(2)3/h4-5,8-9,15H,6-7H2,1-3H3
  • Key:BZFGYTBVFYYKOK-UHFFFAOYSA-N

O-Acetylbufotenine, or bufotenine O-acetate, also known as 5-acetoxy-N,N-dimethyltryptamine (5-AcO-DMT) or O-acetyl-N,N-dimethylserotonin, is a synthetic tryptamine derivative and putative serotonergic psychedelic.[1][2][3] It is the O-acetylated analogue of the naturally occurring peripherally selective serotonergic tryptamine bufotenine (5-hydroxy-N,N-dimethyltrypamine or N,N-dimethylserotonin) and is thought to act as a centrally penetrant prodrug of bufotenine.[1][2][3]

Bufotenine has low lipophilicity, limitedly crosses the blood–brain barrier in animals, does not produce psychedelic-like effects in animals except at very high doses or administered directly into the brain, and produces inconsistent and weak psychedelic effects accompanied by pronounced peripheral side effects in humans.[1][4][5][3] O-Acetylbufotenine, which is much more lipophilic than bufotenine due to its acetyl group, was developed in an attempt to overcome bufotenine's limitations and allow for the drug to efficiently cross the blood–brain barrier.[1][3] In contrast to peripherally administered bufotenine, O-acetylbufotenine readily enters the brain in animals and produces robust psychedelic-like effects.[1][2] In addition, O-acetylbufotenine was more potent than N,N-dimethyltryptamine (DMT) or 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT; O-methylbufotenine) in animals.[1][2] However, the effects of O-acetylbufotenine in humans have not been assessed or reported.[1] Alexander Shulgin speculated about O-acetylbufotenine in TiHKAL but did not personally synthesize or test it.[3]

O-Acetylbufotenine is thought to be a prodrug of bufotenine, which is a non-selective agonist of many of the serotonin receptors, including of the serotonin 5-HT2A receptor (the activation of which is associated with psychedelic effects).[4][6][5] However, O-acetylbufotenine has also unexpectedly been found to act directly as an agonist of certain serotonin receptors, including of the serotonin 5-HT1A and 5-HT1D receptors.[7][8]

The O-acetyl substitution of O-acetylbufotenine is expected to be cleaved quite rapidly in vivo, which may hinder the ability of O-acetylbufotenine to cross the blood–brain barrier and deliver bufotenine into the central nervous system.[1] Because of this, other O-acyl derivatives of bufotenine besides O-acetylbufotenine have been developed and studied.[1][7] One such analogue, O-pivalylbufotenine, has been assessed and has likewise been shown to produce psychedelic-like effects animals.[1][2][7]

O-Acetylbufotenine was first described in the scientific literature by 1968.[9][10]

See also

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References

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  1. ^ a b c d e f g h i j 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. In an effort to overcome this problem of poor lipid solubility, Gessner et al. [20] prepared 5-acetoxy DMT (i.e., O-acetyl bufotenine), which was found to possess a greater lipid solubility than bufotenine, and, which should be hydrolyzed to bufotenine once it has entered the brain. Animal studies reveal that 5-acetoxy DMT is behaviorally active, and more active than either DMT or 5-OMe DMT [17]. No human studies have been performed with 5-acetoxy bufotenine.
  2. ^ a b c d e Nichols DE, Glennon RA (1984). "Medicinal Chemistry and Structure-Activity Relationships of Hallucinogens" (PDF). Hallucinogens: Neurochemical, Behavioral, and Clinical Perspectives. pp. 95–142. Bufotenine has been found to be behaviorally inactive, or only weakly active, in most animal studies, although at 15 mg/kg, it did produce the head-twitch resonse in mice (43). It was also behaviorally active in experiments in which the blood-brain barrier was bypassed (78). Acylation of the polar hydroxy group of bufotenine increases its lipid solubility (65, 74) and apparently enhances its ability to cross the blood-brain barrier (64). For example, O-acetylbufotenine (5-acetoxy-N,N-dimethyltryptamine; 54) disrupted conditioned avoidance behavior in rodents (65) and produced tremorigenic activity similar to that elicited by DMT (37) or 5-OMeDMT (59) when administered to mice (64). In this latter study, a comparison of brain levels Of bufotenine after administration of O-acetylbufotenine with those of DMT and 5-OMeDMT revealed bufotenine to be the most active of the three agents, based on brain concentration. The pivaloyl ester of bufotenine also appears to possess behavioral activity, since stimulus generalization was observed when this agent was administered to animals trained to discriminate 5-OMeDMT from saline (74).
  3. ^ a b c d e Shulgin & Shulgin. TiHKAL #19. 5-HO-DMT
  4. ^ a b McBride MC (2000). "Bufotenine: toward an understanding of possible psychoactive mechanisms". J Psychoactive Drugs. 32 (3): 321–331. doi:10.1080/02791072.2000.10400456. PMID 11061684.
  5. ^ a b Neumann J, Dhein S, Kirchhefer U, Hofmann B, Gergs U (2024). "Effects of hallucinogenic drugs on the human heart". Front Pharmacol. 15: 1334218. doi:10.3389/fphar.2024.1334218. PMC 10869618. PMID 38370480.
  6. ^ Plazas E, Faraone N (February 2023). "Indole Alkaloids from Psychoactive Mushrooms: Chemical and Pharmacological Potential as Psychotherapeutic Agents". Biomedicines. 11 (2): 461. doi:10.3390/biomedicines11020461. PMC 9953455. PMID 36830997.
  7. ^ a b c Glennon RA, Gessner PK, Godse DD, Kline BJ (November 1979). "Bufotenine esters". J Med Chem. 22 (11): 1414–1416. doi:10.1021/jm00197a025. PMID 533890.
  8. ^ Glennon RA, Hong SS, Bondarev M, Law H, Dukat M, Rakhi S, Power P, Fan E, Kinneau D, Kamboj R, Teitler M, Herrick-Davis K, Smith C (January 1996). "Binding of O-alkyl derivatives of serotonin at human 5-HT1D beta receptors". Journal of Medicinal Chemistry. 39 (1): 314–22. doi:10.1021/jm950498t. PMID 8568822.
  9. ^ Gessner PK, Godse DD, Krull AH, McMullan JM (March 1968). "Structure-activity relationships among 5-methoxy-n:n-dimethyltryptamine, 4-hydroxy-n:n-dimethyltryptamine (psilocin) and other substituted tryptamines". Life Sci. 7 (5): 267–77. doi:10.1016/0024-3205(68)90200-2. PMID 5641719.
  10. ^ Gessner PK, Dankova JB (January 1975). "Brain Bufotenine from Administered Acetylbufotenine: Comparison of Its Tremorgenic Activity with That of N,N-Dimethyltryptamine and 5-Methoxy-N,N-Dimethyltryptamine". Pharmacologist. 17 (2): 259.


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