Metabolic study of 2,5-dimethoxy-4-ethylamphetamine (DOET) in rats.
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DOM 2,5-Dimethoxy-4-Methylamphetamine↗
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Metabolic O-demethylation of the psychotomimetic amine 1-(2, 5-dimetroxy-4-methylphenyl)-2-aminopropane.
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.
DOM 2,5-Dimethoxy-4-Methylamphetamine↗
Fourier transform infrared/Raman differentiation and characterization of cis- and trans-2,5-dimethoxy-4,beta-dimethyl-beta-nitrostyrenes: precursors to the street drug STP.
Fourier transform Raman and infrared spectra of pure cis(Z)- and trans(E)-2,5-dimethoxy-4,beta-dimethyl-beta-nitrostyrene (precursors of the psychotomimetic street drug STP or DOM) were recorded in the solid state. The spectra show characteristic features of the ethylene moiety and of the aryl and nitro substituents which permit ready differentiation and identification of these isomers. A very strong Raman line at 1670 cm-1 from the cis isomer for the C=C stretching mode, in comparison with a strong Raman line at 1641 cm-1 for the trans isomer, affords primary differentiation of these substances. A second characteristic, of both the Raman and infrared (IR) spectra, is that the frequency of the strong symmetric nitro (NO2) stretching band is about 40 cm-1 higher in the cis (1346 cm-1) than the trans isomer (1301 cm-1). All major IR and Raman bands are reported and given vibrational assignments.
DOM 2,5-Dimethoxy-4-Methylamphetamine↗
5-HT2 receptor-stimulated calcium influx in ovine uterine artery in late pregnancy.
The effects of 5-hydroxytryptamine (5-HT) and 2,5-dimethoxy-4-methyl-amphetamine (DOM) on the Ca2+ influx in the ovine uterine artery in late pregnancy have been studied by measuring 45Ca2+ uptake. Both 5-HT and DOM (2.5 x 10(-8) M to 2.5 x 10(-5) M) induced concentration-dependent rises in 45Ca2+ uptake in the ovine uterine artery, from a basal level of 30.5 +/- 3.5 muMoles/kg wet tissue to peak levels of 91.1 +/- 9.2 and 84.2 +/- 8.1 muMoles/kg wet tissue, respectively. The Ca2+ influx evoked by 5-HT and DOM was inhibited by ketanserin in a concentration-dependent manner. Methiothepin (2.5 x 10(-7) M) also inhibited 5-HT-induced (2.5 x 10(-6) M) Ca2+ influx by 86%. No antagonism was found with 2.5 x 10(-6) M of 3-tropanyl-3,5-dichlorobenzoate (MDL 72222). The contraction elicited to 5-HT (10(-6) M) and DOM (10(-6) M) was blocked by D600 (10(-6) M) which also blocked the contraction produced to KCl (9 x 10(-2) M). Amrinone (10(-5) M) had no inhibitory effect on these contractions. In accord with the results of the contraction study, D600 (2.5 x 10(-6) M) blocked the Ca2+ influx stimulated by 5-HT (2.5 x 10(-6) M) and amrinone (2.5 x 10(-5) M) failed to inhibit 5-HT-induced Ca2+ influx. Nifedipine (2.5 x 10(-6) M) did not antagonize the influx of Ca2+ induced by 5-HT. Sodium nitroprusside inhibited the 5-HT-induced Ca2+ influx, indicating that at least part of its inhibitory effect on the vasoconstriction evolved by 5-HT is due to the inhibition of the influx of Ca2+.
DOM 2,5-Dimethoxy-4-Methylamphetamine↗
The 5-hydroxytryptamine2 agonist, (+-)-1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane stimulates the hypothalamic-pituitary-adrenal (HPA) axis. I. Acute effects on HPA axis activity and corticotropin-releasing factor-containing neurons in the rat brain.
Corticotropin-releasing factor (CRF) is the major physiological regulator of adrenocorticotrophic hormone (ACTH) secretion from the anterior pituitary. In vivo and in vitro studies have suggested that hypothalamic CRF secretion is under stimulatory serotonergic control, although the receptor subtype(s) responsible have not been definitely determined. The acute effects of the 5-hydroxytryptamine2 agonist, (+-1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane (DOB), were examined on a number of biochemical indices of hypothalamic-pituitary-adrenal axis activity in vivo. DOB increased plasma ACTH and corticosterone concentrations at doses greater than 0.1 mg/kg. This effect is dose-dependent. Peak effects occurred 30 min postinjection and returned to basal levels by 4 hr after DOB injection. These effects of DOB are hypothesized to be mediated by the release of hypothalamic CRF because pretreatment with the CRF receptor antagonist (alpha-helical CRF9-41) significantly attenuated the ACTH response to DOB. Median eminence CRF content was also decreased following DOB administration in the presence of the protein synthesis inhibitor, cycloheximide (200 mg/kg i.p.), suggestive of release of CRF from median eminence terminals as a result of DOB activation of CRF neurons. DOB administration was without effect on brain CRF concentrations in all of the 12 extrahypothalamic brain regions studied 60 min after injection. These results, taken together, support a stimulatory role for 5-hydroxytryptamine2 receptors on hypothalamic CRF secretion.
DOM 2,5-Dimethoxy-4-Methylamphetamine↗
The 5-hydroxytryptamine2 agonist, (+-)-1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane stimulates the hypothalamic-pituitary-adrenal (HPA) axis. II. Biochemical and physiological evidence for the development of tolerance after chronic administration.
In order to investigate the long term effects of the 5-hydroxytryptamine2 (5-HT2) receptor agonist, (+-)-1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane (DOB), on hypothalamic-pituitary-adrenal (HPA) axis activity, DOB (0.35 mg/kg/day) was administered via osmotic minipumps to rats for 7 days at which time plasma adrenocorticotrophic hormone (ACTH), corticosterone and regional brain corticotropin-releasing factor (CRF) concentrations were measured. In addition, anterior pituitary CRF and frontal cortical 5-HT2 receptor binding was measured. Seven-day infusion of DOB resulted in tolerance to the stimulatory actions of the drug on the HPA axis as evidenced by the return of plasma ACTH and corticosterone concentrations to base-line values. Moreover, rats treated chronically with DOB exhibited decreased numbers of both anterior pituitary CRF and cortical and hypothalamic 5-HT2 receptor. These receptor changes were physiologically significant as challenges doses of DOB or CRF resulted in blunted ACTH responses. Chronic DOB infusion was without effect on CRF concentrations in all hypothalamic and extrahypothalamic brain regions studied. A series of time course experiments revealed that DOB-induced increases in plasma corticosterone returned to base-line by 2-days postimplantation. This effect was apparently associated with down-regulation of the 5-HT2 receptor because high-affinity cortical [3H]DOB and hypothalamic (+-)-[125I]-1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane binding were decreased at this time as well. Although median eminence CRF content was unchanged at all time points, anterior pituitary CRF receptor binding was significantly decreased 7 days postimplantation.(ABSTRACT TRUNCATED AT 250 WORDS)
DOM 2,5-Dimethoxy-4-Methylamphetamine↗
Electrophysiological characterization of 5-hydroxytryptamine2 receptors in the rat medial prefrontal cortex.
The aim of the present study was to characterize 5-hydroxytryptamine2 (5-HT2) receptors in the rat medial prefrontal cortex (mPFc) by single cell recording and microiontophoretic techniques. This was accomplished using 5-HT2 receptor agonists 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane [(+/-)-DOI] and 1-[2,5-dimethoxy-4-bromophenyl]-2-aminopropane [(+/-)-DOB]. DOI ejected at a low current (0.5 nA) potentiates glutamate (GLU)-induced activation of mPFc neurons and this effect is blocked by spiperone. At higher currents. DOI invariably inhibits GLU-induced neuronal activity. The microiontophoretic ejection of both DOI and DOB predominantly inhibits spontaneously active mPFc cells. The inhibitory action of DOI on spontaneously active cells is dose-dependent and is blocked by putative 5-HT2 receptor antagonists, with a rank order of potency as follows: ritanserin greater than metergoline approximately LY-53857 greater than spiperone greater than mesulergine greater than mianserin approximately ketanserin. Interestingly, ketanserin and mianserin only weakly block the effect of DOI. The suppressant action of DOI is probably not related to its interaction with 5-HT10 sites as spiperone, which has low affinity for these sites, potently blocks the effect of DOI. The suppressant effect of DOI is not blocked by other receptor antagonists such as BRL-43694 (5-HT3), (+/-)-pindolol (5HT 1a,1b, beta adrenergic, beta), prazosin (adrenergic1, alpha-1), pyrilamine (histamine1, H1), l-sulpiride (dopamine2, D2) or SR 95103 (gamma-aminobutyric acid, GABAA). Overall our results indicate that DOI predominantly inhibits mPFc cells in a direct manner and this effect is mediated by 5-HT2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
DOM 2,5-Dimethoxy-4-Methylamphetamine↗
Characterization of serotonergic receptors mediating contraction of ovine umbilical artery.
Responses to serotonergic agonists were studied in isolated umbilical arteries obtained from fetal lambs within 2 weeks of term. The order of potency of the agonists was determined to be 2,5-dimethoxy-4-methyl-amphetamine (DOM) greater than 5-hydroxytryptamine (5-HT) greater than alpha-methyl-5-HT greater than 1-(3-chlorophenyl) piperazine = m-trifluoromethyl-phenylpiperazine greater than 8-hydroxy-dipropylaminotetralin greater than 2-methyl-5-HT greater than 1-(2-methoxyphenyl) piperazine. Variations in the sensitivity and potency of the agonists results primarily from the variation in the affinity for the 5-HT2 receptor and less so in the efficacy, alpha-Methyl-5-HT was a full agonist compared to 5-HT. The others were partial agonists. The mean KA values for 5-HT and DOM were 4.71 +/- 0.62 x 10(-7) and 0.36 +/- 0.04 x 10(-7) M, respectively. Contractions to 5-HT and DOM were antagonized by ketanserin with pA2 values being 9.4 and 9.1, respectively, suggesting that they act on the same receptor and that their responses are mediated by 5-HT2 receptors. Contractile responses to 8-hydroxy-dipropylaminotetralin, 2-methyl-5-HT and the phenylpiperazines [m-trifluoromethyl-phenylpiperazine and 1-(3-chlorophenyl) piperazine] were also blocked by ketanserin (10(-8) M), indicating that contractions produced by these agonists were mediated by 5-HT2 receptors. No antagonism by MDL 72222 (3-tropanyl-3,5-dichlorobenzoate) of responses to 5-HT indicates that 5-HT3 receptors are not present in this tissue.
DOM 2,5-Dimethoxy-4-Methylamphetamine↗
[3H]-DOB(4-bromo-2,5-dimethoxyphenylisopropylamine) and [3H] ketanserin label two affinity states of the cloned human 5-hydroxytryptamine2 receptor.
The binding properties of the 5-hydroxytryptamine2 (5-HT2) receptor have been the subject of much interest and debate in recent years. The hallucinogenic amphetamine derivative 4-bromo-2,5-dimethoxyphenylisopropylamine (DOB) has been shown to bind to a small number of binding sites with properties very similar to [3H]ketanserin-labeled 5-HT2 receptors, but with much higher agonist affinities. Some researchers have interpreted this as evidence for the existence of a new subtype of 5-HT2 receptor (termed 5-HT2A), whereas others have interpreted these data as indicative of agonist high affinity and agonist low affinity states for the 5-HT2 receptor. In this investigation, a cDNA clone encoding the serotonin 5-HT2 receptor was transiently transfected into monkey kidney Cos-7 cells and stably transfected into mouse fibroblast L-M(TK-) cells. In both systems, expression of this single serotonin receptor cDNA led to the appearance of both [3H]DOB and [3H]ketanserin binding sites with properties that matched their binding characteristics in mammalian brain homogenates. Addition of guanosine 5'-(beta, gamma-imido) triphosphate [Gpp(NH)p] to this system caused a rightward shift and steepening of agonist competition curves for [3H] ketanserin binding, converting a two-site binding curve to a single low affinity binding state. Gpp(NH)p addition also caused a 50% decrease in the number of high affinity [3H]DOB binding sites, with no change in the dissociation constant of the remaining high affinity states. These data on a single human 5-HT2 receptor cDNA expressed in two different transfection host cells indicate that [3H]DOB and [3H]ketanserin binding reside on the same gene product, apparently interacting with agonist and antagonist conformations of a single human 5-HT2 receptor protein. These observations are consistent with the classical view of interconvertible agonist affinity states of GTP-binding protein-coupled receptors and strongly support the "two state" over the "two receptor" model for DOB binding to the 5-HT2 receptor.
DOM 2,5-Dimethoxy-4-Methylamphetamine↗
Characterization of 5-hydroxytryptamine receptors on isolated ovine uterine artery in late pregnancy.
5-Hydroxytryptamine (5-HT) and 2,5-dimethoxy-4-methyl-amphetamine (DOM) are potent agonists on isolated ovine uterine arteries in late pregnancy. Similar pA2 values (8.56 and 8.33, respectively) of ketanserin, tested against 5-HT and DOM, indicate that responses produced by both agonists are mediated by the 5-HT2 receptor. The contractions produced by 8-OH-DPAT and 2-methyl-5-HT were also blocked by ketanserin (10(-8) M) with the dissociation constants (KB) being 2.49 and 2.88 nM, respectively. This provides evidence that these agonists are activating 5-HT2 receptors in the ovine uterine artery. DOM was more potent than 5-HT, but had a similar efficacy to that of 5-HT. The greater affinity of DOM may explain its greater potency. The dissociation constants (KA) of 5-HT and DOM acting on 5-HT receptors were determined by analysis of concentration-response data before and after fractional inactivation of receptors with dibenamine. The mean KA values for 5-HT and DOM were 3.7 +/- 0.7 x 10(-7) and 1.8 +/- 0.3 x 10(-7) M, respectively. Assessment of receptor occupancy vs. functional response demonstrated little or no receptor reserve in this tissue. Several other 5-HT receptor agonists caused contractions but were much less potent than 5-HT. The order of potency of these agonists was determined to be DOM greater than 5-HT greater than or equal to alpha-methyl-5-HT much greater than 8-hydroxy-dipropylaminotetralin (8-OH-DPAT) greater than 2-methyl-5-HT greater than 1-(3-chlorophenyl) piperazine (mCPP) greater than m-trifluoromethyl-phenylpiperazine (TFMPP).(ABSTRACT TRUNCATED AT 250 WORDS)
DOM 2,5-Dimethoxy-4-Methylamphetamine↗
Effects of McN-6186 on voltage-dependent Ca++ channels in heart and pituitary cells.
McN-6186 (N-[2-(3,5-dimethoxyphenyl)ethyl]-5-methoxy-alpha-methyl-2 -(phenylethynyl) benzeneethanamine hydrochloride is a compound structurally distinct from other Ca++ channel ligands. McN-6186 showed some stimulation of 1,4-dihydropyridine-sensitive Ca++ uptake in neonatal rat ventricular cells at concentrations of 1 and 3 nM. At higher concentrations McN-6186 inhibited this uptake in rat ventricular cells at concentrations approximately 100-fold less than those needed to block the corresponding Ca++ uptake in rat anterior pituitary (GH3) cells. McN-6186 (2 microM) inhibited L-type Ca++ channel current in neonatal rat ventricular cells in a voltage-dependent manner while having little or no effect on this current in GH3 cells. In some ventricular cells tested, the T-type Ca++ current was also blocked by 2 microM McN-6186. McN-6186 inhibited (+)-[3H]PN200-110 binding in rat cardiac membranes with an IC50 value of 1.45 X 10(-7) M and a shallow Hill slope (nH = 0.42). It is concluded that McN-6186 blocks L-type Ca++ channels in heart cells preferentially to those found in GH3 cells. Furthermore, McN-6186 may have other sites and mechanisms of action in addition to L-type Ca++ channel blockade.
DOM 2,5-Dimethoxy-4-Methylamphetamine↗
[Studies on the identification of psychotropic substances. VI. Preparation and various analytical data of reference standards of some hallucinogens, 2,5-dimethoxy-4-methylamphetamine (STP), 2,5-dimethoxy-4-bromoamphetamine (DOB) and 2,5-dimethoxy-4-ethylamphetamine (DOET)].
The Reference Standards of 2,5-dimethoxy-4-methylamphetamine (STP), 2,5-dimethoxy-4-bromoamphetamine (DOB) and 2,5-dimethoxy-4-ethylamphetamine (DOET) were prepared. Their purities measured by HPLC were 99.5% for STP hydrochloride, 99.8% for DOB hydrobromide and 99.5% for DOET hydrochloride. For the identification and determination, various analytical data of the three drugs were obtained by using UV, IR, HPLC, GC/MS and NMR, and the discrimination were discussed.
DOM 2,5-Dimethoxy-4-Methylamphetamine↗
Comparative effects of hallucinogenic drugs on behavior of the cat.
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DOM 2,5-Dimethoxy-4-Methylamphetamine↗
A new interpretation of the involvement of serotonin in delayed-type hypersensitivity. Serotonin-2 receptor antagonists inhibit contact sensitivity by an effect on T cells.
5-HT is a neuromediator and a vasoactive amine released by platelets and murine mast cells at sites of inflammation. A role for 5-HT has been proposed in murine DTH and has been attributed to its 5-HT2R-dependent vasoactive properties. We have tested the hypothesis that the role of 5-HT in DTH is related to an interaction of 5-HT with DTH effector T cells. In vivo treatment of sensitized mice with the 5-HT2R antagonists methysergide or ketanserin inhibited both their capacity to elicit DTH and the ability of their lymphoid cells to transfer DTH. In vitro treatment of lymphoid cells, or of nylon wool-purified T cells from sensitized mice, with 10(-7) to 10(-9) M of the 5-HT2R antagonists methysergide, ketanserin, ritanserin, or LY 53857, followed by three washings, inhibited as strongly their ability to transfer DTH, both systemically or locally. Systemic and local co-transfer experiments of 5-HT2R antagonist-treated and untreated cells indicated that this inhibition was not related to the induction of suppression. 5-HT2R antagonist treatment was nontoxic to T cells; did not affect the in vitro response of T cells to mitogen; selectively inhibited the efferent, but not the afferent limb of DTH; and in the efferent T cell cascade, affected the late-acting (24 h) inflammatory DTH T cells, but not the early-acting, DTH-initiating T cells. 5-HT2R selectivity was suggested by the absence of effect of an alpha-adrenergic R antagonist, and by prevention of the inhibitory effect of a 5-HT2R antagonist by prior incubation with the selective 5-HT2R agonist 1-(2,5-dimethoxy phenyl-4-methyl)-2 aminopropane. In summary, inhibition of DTH effector T cell function appeared sufficient, independently of any vascular effect, to account for the in vivo inhibitory effect of 5-HT2R antagonists on the elicitation of DTH. Our data suggest that late-acting DTH effector T cells might express functional 5-HT2R, and that these receptors might require in vivo activation in order for the T cells to locally produce the inflammatory lymphokine-dependent aspects of DTH.
DOM 2,5-Dimethoxy-4-Methylamphetamine↗
Lysergic acid diethylamide and 2,5-dimethoxy-4-methylamphetamine are partial agonists at serotonin receptors linked to phosphoinositide hydrolysis.
Based on electrophysiological, radioligand binding, and behavioral studies in laboratory animals, it is generally believed that the psychotomimetic effects of the phenethylamine and indolealkylamine hallucinogens are mediated by central serotonin (5-HT) receptors, in particular the 5-HT-2 subtype. Agonist-stimulated phosphoinositide hydrolysis was utilized to determine the potency and efficacy of racemic 1-(2,5)-dimethoxy-4-methyl-phenyl)-2-aminopropane (DOM), and d-lysergic acid diethylamide (LSD) at the 5-HT-2 receptor in rat cerebral cortex and the 5-HT-1c receptor in rat choroid plexus. Both DOM and LSD stimulated phosphoinositide hydrolysis in cerebral cortex. These effects were blocked by the 5-HT-2 antagonists, ketanserin and spiperone, but not by antagonists of muscarinic, alpha-1 adrenergic or histaminergic receptors. The maximum responses of DOM and LSD, respectively, were 76% and 25% of the maximum response to 5-HT. However, LSD was 500 times more potent than was racemic DOM. Consistent with a partial agonist effect, LSD partially blocked the effect of 5-HT, with a maximal inhibition equivalent to the intrinsic activity of LSD alone. In choroid plexus, DOM and LSD stimulated phosphoinositide hydrolysis and both responses were blocked by mianserin and less effectively by spiperone. The maximum effect of DOM was 67% of that of 5-HT, whereas the maximum effect of LSD was only 34% of the maximum response of 5-HT. LSD was 50 times more potent than was racemic DOM. LSD partially antagonized the effect of 5-HT in the choroid plexus, consistent with a partial agonist effect at the 5-HT-1c receptor in this tissue.(ABSTRACT TRUNCATED AT 250 WORDS)
DOM 2,5-Dimethoxy-4-Methylamphetamine↗
An economical screen for phenethylamine-type hallucinogens: mouse ear scratching.
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DOM 2,5-Dimethoxy-4-Methylamphetamine↗
Triphasic dose-lethality relationships for amphetamine and certain ring-substituted amphetamines in isolated or aggregated mice.
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DOM 2,5-Dimethoxy-4-Methylamphetamine↗
Gas chromatographic analysis of amphetamine derivatives and morpholine-related drugs.
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DOM 2,5-Dimethoxy-4-Methylamphetamine↗