Application of chemical ionization mass spectrometry to the study of stereoselective in vitro metabolism of 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane

Weinkam, Robert J.; Gál, J.; Callery, Patrick S.; Castagnoli, Neal

doi:10.1021/ac60365a058

Cited by 16 publications

(8 citation statements)

References 28 publications

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“…The fact that oxidative deamination represents only a minor pathway for DOM metabolism (Ho et al 1971; Matin et al 1974; Weinkam et al 1976; Zweig and Castagnoli 1977) is consistent with the lack of an interaction between harmaline pretreatment and DOM. However, the existence of a purely metabolic interaction between 5-MeO-DMT and MAO A inhibition does not explain why the behavioral profile associated with 5-MeO-DMT-induced 5-HT 2A receptor activation is shifted from hypoactivity to hyperactivity in the presence of harmaline or clorgyline.…”

Section: Discussionsupporting

confidence: 64%

Modification of the effects of 5-methoxy-N,N-dimethyltryptamine on exploratory behavior in rats by monoamine oxidase inhibitors

et al. 2008

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RATIONALE The hallucinogenic tea known as ayahuasca is made from a combination of psychoactive plants that contribute the active components N,N-dimethyltryptamine (DMT) and 5-methoxy-DMT (5-MeO-DMT), as well as the monoamine oxidase (MAO) inhibitors (MAOIs) harmine and harmaline for oral activity. OBJECTIVE The present study examined the effects of 5-MeO-DMT in combination with MAOIs in rats using the Behavioral Pattern Monitor (BPM), which enables analyses of patterns of locomotor activity and exploration. Interaction studies using the serotonin (5-HT)1A antagonist WAY-100635 (1.0 mg/kg) and the 5-HT2A antagonist MDL 11,939 (1.0 mg/kg) were also performed to assess the respective contributions of these receptors to the behavioral effects of 5-MeO-DMT in MAOI-treated animals. RESULTS 5-MeO-DMT (0.01, 0.1, and 1.0 mg/kg) decreased locomotor activity and investigatory behavior. In rats pretreated with a behaviorally inactive dose of harmaline (0.1 mg/kg), 1.0 mg/kg 5-MeO-DMT had biphasic effects on locomotor activity, initially reducing locomotion and then increasing activity as time progressed. The ability of harmaline to shift 5-MeO-DMT to a biphasic locomotor pattern was shared by the selective MAOA inhibitor clorgyline, whereas the selective MAOB inhibitor (−)-deprenyl was ineffective. The late hyperactivity induced by the combination of 1.0 mg/kg 5-MeO-DMT and 0.3 mg/kg clorgyline was blocked by pretreatment with MDL 11,939. Pretreatment with WAY-100635 failed to attenuate either the early hypoactivity or the late hyperactivity. CONCLUSIONS The ability of harmaline to modify the behavioral effects of 5-MeO-DMT is mediated by inhibition of MAOA. Further, 5-HT2A receptors are responsible for the late hyperactivity induced by 5-MeO-DMT in the presence of MAOA inhibitors.

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Section: Discussionsupporting

confidence: 64%

Modification of the effects of 5-methoxy-N,N-dimethyltryptamine on exploratory behavior in rats by monoamine oxidase inhibitors

et al. 2008

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“…The inability to generate significant amounts of these metabolites, coupled with the high observed in uitro activity for 11, argues against this possibility. Weinkam et al (126) confirmed that the p -hydroxymethyl derivative is the major metabolite in rabbit liver microsome preparations. Weinkam et al (126) confirmed that the p -hydroxymethyl derivative is the major metabolite in rabbit liver microsome preparations.…”

Section: Effects Of Distribution and Metabolismmentioning

confidence: 94%

Structure-Activity Relationships of Phenethylamine Hallucinogens

Nichols

1981

Journal of Pharmaceutical Sciences

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“…This effect has been suggested to arise from the selective metabolism of the less active enantiomer. Indeed, both in vitro and in vivo metabolism studies with 1-phenyl-2-aminopropanes, such as 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane and amphetamine, have demonstrated the occurrence of stereoselective metabolism (Weinkam et al, 1976;Gunaratna and Kissinger, 1998). An evaluation of the metabolism of DOI and its enantiomers in ocular tissues is therefore warranted in view of the dramatically different IOP reduction responses observed for the enantiomers of this compound.…”

mentioning

confidence: 99%

Evaluation of the Ocular Hypotensive Response of Serotonin 5-HT_1A and 5-HT₂ Receptor Ligands in Conscious Ocular Hypertensive Cynomolgus Monkeys

May¹,

McLaughlin²,

Sharif³

et al. 2003

J Pharmacol Exp Ther

106

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Published investigations of serotonin-1A (5-hydroxytryptamine 1A ; 5-HT 1A ) receptor agonists and serotonin-2A (5-hydroxytryptamine 2A ; 5-HT 2A ) receptor antagonists in nonprimate species provide conflicting results with regard to their intraocular pressurelowering efficacy. Thus, their therapeutic utility in the treatment of human glaucoma has been confusing. We evaluated the effect of selected 5-HT 1A agonists and 5-HT 2A receptor antagonists on intraocular pressure in a nonhuman primate model, the conscious cynomolgus monkey with laser-induced ocular hypertension. Neither selective 5-HT 1A agonists [e.g., R-8-hydroxy-2-(di-n-propylamino)tetralin and flesinoxan] nor selective 5-HT 2 receptor antagonists [e.g.,pressure in the primate model following topical ocular administration. However, compounds that function as agonists at both the 5-HT 1A and 5-HT 2 receptors were found to effectively lower intraocular pressure in the model: 5-hydroxy-␣-methyltryptamine, 5-methoxy-␣-methyltryptamine, 5-hydroxy-N,N-dimethyltryptamine (bufotenine), and 5-methoxy-N,N-dimethyltryptamine. Furthermore, the selective 5-HT 2 receptor agonist R-(Ϫ)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane lowered intraocular pressure in the primate model, demonstrating a pharmacological response associated with activation of the 5-HT 2 receptor. These observations suggest that compounds that function as efficient agonists at 5-HT 2 receptors should be considered as potential agents for the control of intraocular pressure in the treatment of ocular hypertension and glaucoma in humans.Identification of several of the numerous serotonin receptors in ocular tissues of the anterior segment of the eye, including the iris-ciliary body of rabbit (Chidlow et al., 1998) and human (Martin et al., 1992), suggests that this neurotransmitter may play an important role in the regulation of intraocular pressure (IOP). Serotonin (5-hydroxytryptamine; 5-HT) is also found in the aqueous humor of humans (Veglio et al., 1998) and other mammals (Boerrigter et al., 1992). These observations have generated considerable interest in the role that serotonin might have in aqueous humor dynamics and even whether 5-HT might be involved in the development of ocular hypertension and glaucoma. There have been numerous conflicting reports on the effect of 5-HT and various 5-HT receptor ligands on IOP in the rabbit, dog, and humans. These observed differences in IOP response may be due to species differences, route of administration, or the lack of 5-HT receptor selectivity of the agents evaluated. For example, 5-HT has been shown to lower IOP in rabbits following intravenous injection (Chiang, 1974). However, when injected intracamerally in the rabbit, a rise in IOP was observed (Krootila et al., 1987). Furthermore, topical ocular administration of 5-HT to the rabbit was reported to result in either a decrease (Krootila et al., 1987) or an increase (Meyer-Bothling et al., 1993) in IOP.Article, publication date, and citation information can be found at

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Application of chemical ionization mass spectrometry to the study of stereoselective in vitro metabolism of 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane

Cited by 16 publications

References 28 publications

Modification of the effects of 5-methoxy-N,N-dimethyltryptamine on exploratory behavior in rats by monoamine oxidase inhibitors

Modification of the effects of 5-methoxy-N,N-dimethyltryptamine on exploratory behavior in rats by monoamine oxidase inhibitors

Structure-Activity Relationships of Phenethylamine Hallucinogens

Evaluation of the Ocular Hypotensive Response of Serotonin 5-HT_1A and 5-HT₂ Receptor Ligands in Conscious Ocular Hypertensive Cynomolgus Monkeys

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Application of chemical ionization mass spectrometry to the study of stereoselective in vitro metabolism of 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane

Cited by 16 publications

References 28 publications

Modification of the effects of 5-methoxy-N,N-dimethyltryptamine on exploratory behavior in rats by monoamine oxidase inhibitors

Modification of the effects of 5-methoxy-N,N-dimethyltryptamine on exploratory behavior in rats by monoamine oxidase inhibitors

Structure-Activity Relationships of Phenethylamine Hallucinogens

Evaluation of the Ocular Hypotensive Response of Serotonin 5-HT1A and 5-HT2 Receptor Ligands in Conscious Ocular Hypertensive Cynomolgus Monkeys

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Product

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Evaluation of the Ocular Hypotensive Response of Serotonin 5-HT_1A and 5-HT₂ Receptor Ligands in Conscious Ocular Hypertensive Cynomolgus Monkeys