DOM
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🧬 Receptor activity
Mechanism of action
Alterations in brain serotonergic function have been implicated in the mechanism of action of LSD, mescaline, and other similarly acting hallucinogenic drugs of abuse such as STP (2,5-dimethoxyphenylisopropylamine; DOM). In order to test the hypothesis that the mechanism of action of LSD and phenylisopropylamine hallucinogens is through stimulation of a specific brain serotonin receptor sub-type, the affinities of these compounds for radiolabelled 5-HT2, 5-HT1A, 5-HT1B, and 5-HT1C receptors have been determined using recently developed in vitro radioligand binding methodologies. The 5-HT2 receptor was labelled with the agonist/hallucinogen radioligand 3H-DOB (4-bromo-2,5-dimethoxyphenylisopropylamine). The 5-HT1A, 5-HT1B, and 5-HT1C receptors were labelled with 3H-OH-DPAT, 3H-5-HT, and 3H-mesulergine, respectively. In general, the phenylisopropylamines displayed 10-100 fold higher affinities for the 5-HT2 receptor than for the 5-HT1C receptor and 100-1000 fold higher affinities for the 5-HT2 receptor than for the 5-HT1A or 5-HT1B receptor. There was a strong correlation between hallucinogenic potencies and 5-HT2 receptor affinities of the phenylisopropylamines (r = 0.90); the correlation coefficients for the 5-HT1A, 5-HT1B, and 5-HT1C were 0.73, 0.85, and 0.78, respectively. Because there is no evidence that 5-HT1A-selective or 5-HT1B-selective agonists are hallucinogenic and because the phenylisopropylamines are potent hallucinogens, a 5-HT2 receptor interaction is implicated and supports previous suggestions to this effect. A secondary role for 5-HT1C receptors cannot be discounted at this time.
2,5-Dimethoxy-4-methylamphetamine (DOM, "STP") is a potent hallucinogen, proposed to be a serotonin receptor agonist. Its effects have not previously been tested upon central neurons where serotonin is excitatory and serotonin antagonists are effective. Extracellular single unit recordings were obtained from facial motoneurons in anesthetized rats, and drugs were applied from five-barrelled micropipettes by iontophoresis. Facial motoneurons were commonly silent. During subthreshold application of glutamate, firing could be induced by dopamine and DOM. As reported by others, serotonin and noradrenaline also excited facial motoneurons under these conditions. Methysergide antagonized responses to serotonin and DOM but not those to noradrenaline; methysergide could not usually discriminate between responses to serotonin and dopamine. Ketanserin reversibly antagonized (but could not discriminate between) responses to serotonin, dopamine, and noradrenaline. Chlorpromazine antagonized responses to dopamine at doses that did not alter serotonin-induced excitation, and responses to DOM were not reduced by doses of chlorpromazine, that had no local anaesthetic effect on action potentials elicited by DOM and serotonin. These results suggest that DOM is an agonist on at least one type of central serotonin receptor. This receptor may also be a ketanserin (5-HT2) binding site.
... In perfused dog forelimb DOM produced a vasodilation followed by a vasoconstriction. The vasoconstriction produced by DOM was not blocked by phentolamine but was antagonized by methysergide. In isolated superfused vascular strips of dog dorsal metatarsal vein, DOM elicited a muscle contraction which was not blocked by phentolamine or cocaine but was antagonized by cinanserin. It was concluded that DOM had a direct stimulatory effect on serotonin receptors. The vasodilation in the perfused forelimb of the dog induced by DOM was not antagonized by propranolol, atropine, pyrilamine or bulbocapnine. ...
Pharmacokinetics
Absorption
DOM produces effects within 1 to 2 hours of ingestion of doses ranging from 2 to 14 mg. Twenty percent of an ingested dose appears unchanged in the urine within 24 hours.
Metabolism
In an effort to more fully characterize the metabolic fate of the psychotomimetic amine (1-(2, 5-dimethoxy-4-methylpheny)-2-aminopropane (DOM, STP), the formation of the two possible monophenols and the p-hydroquinone metabolites of the parent drug by 10,000 X g supernatent fractions of rabbit liver homogenates has been investigated. All three metabolites have been fully characterized and quantitatively estimated by chemical ionization mass spectrometry with the aid of deuterium enriched compounds. The stereochemical course of the mono-O-demethylation reactions has been shown to proceed with enantiomeric enrichment of the S-aminophenols. The mechanistic implications concerning the mode of action of the parent drug and metabolic O-demethylation are discussed.
The possible relationship between metabolism and psychotomimetic activity among the methoxylated 1-phenyl-2-aminopropanes led to our investigation of the in vitro O-demethylation of 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (1, DOM, STP). Employing a sensitive and highly selective stable isotope dilution assay, we observed that rabbit liver homogenates biotransform the amine 1 to its 2-O-demethyl, 5-O-demethyl, and bis (O-demethyl) metabolite metabolites. Both monophenolic metabolites are enriched in their S enantiomers. The bis(O-demethyl) metabolite has structural, chemical, and electrochemical similarities to the sympatholytic agent "6-hydroxydopamine". The possible significance of metabolic O-demethylation in terms of the psychotomimetic properties of amine 1 is discussed.
Metabolites of STP have been synthesized and identified in rat urine and feces. A 4-hydroxymethyl compound which resulted from hydroxylation of the 4-methyl group of STP accounted for half of the total amount of the metabolites isolated in the 24 hour urine. The further oxidation product of the 4-hydroxymethyl compound, the 4-carboxy metabolite and unchanged STP were present in a ratio of 2 to 7. A trace amount of the ketone, derived from oxidation of the side-chain of STP, was also detected. The feces at the same time interval contained almost exclusively the 4-carboxy metabolite, with the 4-hydroxymethyl metabolite and a relatively small quantity of unchanged STP amounting to less than 7%. In the present study /investigators/ attempted to isolate metabolites of STP in monkey and rat brains, as well as in regional areas of the monkey brain for any possible correlation between metabolism and and the behavioral effects.
The designer drug 2,5-dimethoxy-4-methyl-amphetamine (DOM, STP) is known to be extensively metabolized in various species. The current study showed that cytochrome P450 2D6 was the only isoenzyme involved in formation of the main metabolite hydroxy DOM. In addition, the authors' systematic toxicological analysis (STA) procedure using full-scan GC-MS was suitable to prove an intake of a common drug users' dose of DOM by detection of hydroxy DOM in rat urine. Assuming similar metabolism, the described STA procedure should be suitable for proof of an intake of DOM in human urine. However, DOM and/or other metabolites such as deamino-oxo-hydroxy DOM might be the target analyte in urine of CYP2D6 poor metabolizers.
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