BesidesO-pivalylbufotenine, other bufotenineO-acylesters and putative or confirmed bufotenineprodrugs, such asO-acetylbufotenine among others, have been developed and studied.[1][4]
^abcGlennon 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.PMID6757811.No human studies have been performed with 5-acetoxy bufotenine. Because this acetyl derivative is probably hydrolyzed quite rapidly in vivo, several other 5-acyloxy derivatives have been prepared; detailed pharmacology is not yet available on these compounds, although the pivalyl derivative (5-PB) has been found to be behaviorally active in animals [25].
^abNichols 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.ISBN978-0-89004-990-7.OCLC10324237.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 response 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).
^abcGlennon RA, Rosecrans JA (1981). "Speculations on the mechanism of action of hallucinogenic indolealkylamines".Neurosci Biobehav Rev.5 (2):197–207.doi:10.1016/0149-7634(81)90002-6.PMID7022271.Yet another compound which is less active than expected is 5-pivalylbufotenine (5-PB) [20]. Although generalization occurs between 5-PB (which possesses twice the 5-HT receptor affinity of 5-OMe DMT) and 5-OMe DMT (20), the ED50 for generalization is 25 μmol/kg. Being a highly lipid-soluble compound, 5-PB may become highly protein bound in vivo and, as a consequence, extensive hydrolysis of the ester linkage may occur prior to penetration of the blood–brain barrier.
^abcdefGlennon RA, Gessner PK, Godse DD, Kline BJ (November 1979). "Bufotenine esters".J Med Chem.22 (11):1414–1416.doi:10.1021/jm00197a025.PMID533890.Bufotenine (5-hydroxy-N,N-dimethyltryptamine) has been reported to be behaviorally inactive or only very weakly active in man and animals; this may be a consequence of its low partition coefficient and resultant inability to penetrate the blood-brain barrier. The acetyl, propionyl, butyryl, isobutyryl, and pivalyl esters of bufotenine were prepared for future pharmacological evaluation. Unexpectedly, it was found that these esters all possess a relatively high affinity for the serotonin receptors of the isolated rat stomach fundus preparation. A semiquantitative chromatographic measurement of ester hydrolysis suggests that extensive hydrolysis of the esters to bufotenine does not occur under the conditions of the affinity assay.
