Pharmacological modulation of abnormal involuntary DOI-induced head twitch response movements in male DBA/2J mice: II. Effects of D3 dopamine receptor selective compounds.

We recently reported on the characterization of the hallucinogen 2,5-dimethoxy-4-methylamphetamine's (DOI) ability to elicit a head twitch response (HTR) in DBA/2J mice and the ability of D2 vs. D3 dopamine receptor selective compounds to modulate that response. For these studies, the ability of D3 vs. D2 dopamine receptor selective compounds to attenuate the DOI-dependent HTR was examined. WC 10, a D3 dopamine receptor weak partial agonist with 40-fold binding selectivity for D3 vs. D2 dopamine receptors, produced a dose-dependent decrease in the DOI-induced HTR (IC50 = 3.7 mg/kg). WC 44, a D3 receptor selective full agonist, also inhibited the DOI-induced HTR (IC50 = 5.1 mg/kg). The effect of two D3 receptor selective partial agonists, LAX-4-136 and WW-III-55, were also evaluated. These analogs exhibit 150-fold and 800-fold D3 vs. D2 binding selectivity, respectively. Both compounds inhibited the HTR with similar potency but with different maximum efficacies. At 10 mg/kg WW-III-55 inhibited the HTR by 95%, while LAX-4-136 administration resulted in a 50% reduction. In addition, DOI (5 mg/kg) was administered at various times after LAX-4-136 or WW-III-55 administration to compare the duration of action. The homopiperazine analog LAX-4-136 exhibited greater stability. An assessment of our test compounds on motor performance and coordination was performed using a rotarod test. None of the D3 dopamine receptor selective compounds significantly altered latency to fall, suggesting that these compounds a) did not attenuate the DOI-dependent HTR due to sedative or adverse motor effects and b) may have antipsychotic/antihallucinogenic activity.

A fatal intoxication of 2,5-dimethoxy-4-chloroamphetamine: a case report.

Designer drugs appear to be increasing in popularity because of the ease of obtaining these constituents, the lack of ability to identify the substance(s) in routine drug screening, the appeal of the drug(s) being 'safe' due to them being marketed as a 'legal high' and possibly due to stronger restrictions that are being placed on prescription drugs. As components of designer drugs are identified and regulated by the DEA, new constituents, or analogs, of these designer drugs are being manufactured to circumvent legislation. 2,5-Dimethoxy-4-chloroamphetamine (DOC) is a substituted alpha-methylated phenethylamine and acts as a selective serotonin receptor partial agonist. There is limited literature on this particular compound and no literature that attributes death to use of this drug alone. We present a case of a 37-year-old male found at home lying face down next to a book titled 'Psychedelic Chemistry' by Michael Valentine Smith and in the early stages of decomposition. The decedent was a known methamphetamine abuser. A peripheral blood sample collected at autopsy was sent to toxicology for routine analysis. Results yielded negative for the drugs of abuse classes on the enzyme-linked immunosorbent assay screen but was positive for DOC during routine GC-MS analysis. A urine sample collected at autopsy was subjected to a routine urine liquid/liquid analysis via GC-MS, and the specimen was positive for DOC. Quantification analyses showed DOC concentration levels to be 377 ng/mL in iliac blood; 3,193 ng/mL in urine; 3,143 ng/g in liver and 683 ng/g in brain. DOC was not detected in the gastric contents. Caffeine was the only other compound detected in blood and urine. Due to the lack of literature, we believe that this is the first case where death can be attributed to DOC alone.

Food restriction and streptozotocin differentially modify sensitivity to the hypothermic effects of direct- and indirect-acting serotonin receptor agonists in rats.

Food restriction and experimentally-induced diabetes (streptozotocin) can modify serotonin (5-HT) neurotransmission and sensitivity to drugs acting on 5-HT systems. This study examined the effects of food restriction and streptozotocin on the hypothermic effects of the 5-HT(1A) receptor agonist (+)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide (8-OH-DPAT), the 5-HT(2) receptor agonist (+/-)-2,5-dimethoxy-4-methylamphetamine hydrochloride (DOM), the 5-HT releaser fenfluramine, and the selective 5-HT reuptake inhibitor (SSRI) fluoxetine. All four drugs significantly decreased body temperature in free feeding rats. Limiting rats to 10 g/day of food for 7 days decreased body weight and sensitivity to 8-OH-DPAT induced hypothermia, without affecting sensitivity to DOM, fenfluramine, or fluoxetine induced hypothermia. Subsequently, 7 days of free feeding restored body weight and sensitivity to 8-OH-DPAT. Sensitivity to all drugs was significantly decreased 7 days after 50 mg/kg streptozotocin; subsequently, 10 days of insulin replacement restored sensitivity to all drugs. These results extend to body temperature the observation that food restriction and experimentally-induced diabetes differentially modify sensitivity to drugs acting on 5-HT systems and they further suggest that the clinical response to therapeutic drugs acting on 5-HT systems might be impacted by nutritional and insulin status.

Metabolism and toxicological detection of the designer drug 4-iodo-2,5-dimethoxy-amphetamine (DOI) in rat urine using gas chromatography-mass spectrometry.

The amphetamine-derived designer drug 4-iodo-2,5-dimethoxy-amphetamine (DOI) is an upcoming substance on the illicit drug market. In the current study, the identification of its metabolites in rat urine and their toxicological detection in the authors' systematic toxicological analysis (STA) procedure were examined. DOI is extensively metabolized by O-demethylation and beside small amounts of parent compound it was found to be excreted mainly in form of metabolites. The STA procedure using full-scan GC-MS allowed proving an intake of a common drug users' dose of DOI by detection of the two O-demethyl metabolite isomers in rat urine. Assuming similar metabolism, the described STA procedure should be suitable for proof of an intake of DOI in human urine.

Metabolic pathways of 4-bromo-2,5-dimethoxyphenethylamine (2C-B): analysis of phase I metabolism with hepatocytes of six species including human.

4-Bromo-2,5-dimethoxyphenethylamine (2C-B) is a psychoactive designer drug of abuse that is sold under the street names "Venus", "Bromo", "Erox", "XTC" or "Nexus". Concern has been raised because only little is known about its toxicity and metabolism in humans. In the present study we incubated 2C-B with human, monkey, dog, rabbit, rat and mouse hepatocytes to identify the metabolites formed and to determine possible toxic effects as evidenced by an ATP assay. Our data allow construction of the main metabolic pathways of 2C-B. Oxidative deamination results in the 2-(4-bromo-2,5-dimethoxyphenyl)-ethanol (BDMPE) and 4-bromo-2,5-dimethoxyphenylacetic acid (BDMPAA) metabolites. Additionally, 4-bromo-2,5-dimethoxybenzoic acid (BDMBA) can be produced also by oxidative deamination. Further metabolism of BDMPE and BDMPAA may occur by demethylation. Alternatively, the later metabolites can be generated by demethylation of 2C-B followed by oxidative deamination. Two remarkable interspecies differences in metabolism of 2C-B were observed (i) a hitherto unknown metabolite, 4-bromo-2,5-dimethoxy-phenol (BDMP), was identified after incubation only with mouse hepatocytes; (ii) 2-(4-bromo-2-hydroxy-5-methoxyphenyl)-ethanol (B-2-HMPE) was produced by hepatocytes from human, monkey and rabbit but not by dog, rat and mouse. Comparing the toxic effects of 2C-B between hepatocytes of the six examined species we observed only minor interspecies differences. However, large inter-individual differences in susceptibility of hepatocytes from three human donors were observed.

Toxicología de las drogas de síntesis / Synthetic illicit drugs toxicology

Las drogas de síntesis o 'drogas de diseño' son sustancias psicoactivas de uso recreacional que se fabrican en laboratorios clandestinos. La producción, variedad y número de consumidores de estas drogas aumentan cada año en toda Europa, y con ellos los problemas sanitarios derivados de su uso. Estos problemas comprenden tanto sus efectos secundarios o la intoxicación aguda como sus aún no del todo conocidas repercusiones orgánicas a largo plazo, así como la toxicidad de las sustancias de corte, la de los productos residuales originados en la fabricación de la propia droga y su uso combinado con el de otras drogas. Dentro de la denominación de drogas de síntesis se diferencian principalmente cuatro grupos de sustancias muy diferentes: los derivados anfetamínicos, los opioides sintéticos, las arilhexilaminas y los derivados de la metacualona. Esta revisión aporta una descripción sistemática de dichos compuestos y de su efectos físicos y psíquicos. (AU)

Evidence that 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane-induced hypophagia and hyperthermia in rats is mediated by serotonin-2A receptors.

The administration of various doses of the phenylisopropylamine hallucinogen 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) to rats produced dose-related decreases in 1-hr food intake in a food-restricted paradigm and in locomotor activity. DOM also produced dose-related increases in temperature. Pretreatment with propranolol [a beta adrenoceptor antagonist that also has high binding affinity for serotonin (5-HT) 5-HT1A, 5-HT1B and 5-HT2C sites], bemesetron or ondansetron (5-HT3 antagonists) did not attenuate either DOM-induced hypophagia or hyperthermia. In contrast, pretreatment with metergoline (a 5-HT1/5-HT2 antagonist) and ritanserin (a 5-HT2A/5-HT2C antagonist) significantly attenuated both DOM-induced hypophagia and hyperthermia. However, pretreatment with mesulergine (a 5-HT2C/5-HT2A antagonist) significantly attenuated DOM-induced hyperthermia but not hypophagia. On the other hand, spiperone (5-HT1A/5-HT2A/D2 antagonist) pretreatment significantly attenuated DOM-induced hyperthermia but accentuated DOM-induced hypophagia. Daily administration of DOM (1.0 mg kg-1 day-1) produced complete tolerance to its hypophagic effect by day 4 but did not produce cross-tolerance to m-chlorophenylpiperazine-induced hypophagia. In contrast, daily administration of DOM for 7 days did not produce either tolerance to its hyperthermic effect or modify m-chlorophenylpiperazine-induced hyperthermia in rats. These findings suggest that DOM-induced hypophagia and hyperthermia in rats are mediated by stimulation of 5-HT2a receptors.

4-bromo-2,5-dimethoxyamphetamine: psychoactivity, toxic effects and analytical methods.

4-bromo-2,5-dimethoxyamphetamine (bromo-DMA) is a drug of special interest in Australia as it is available in forms which are seldom seen elsewhere in the world. Data of interest to the Forensic Chemist is summarized. The psychoactivity of bromo-DMA is discussed and a number of case histories involving higher doses are related. A description of dosage forms has been included and variations in drug concentration is discussed. Chemical properties and various methods of quantitative and qualitative analysis, including the use of high performance liquid chromatography, mass spectrometry and infra-red spectroscopy are listed.

The protective effects of methysergide, 6-hydroxydopamine and other agents on the toxicity of amphetamine, phentermine, MDA, PMA, and STP in mice.

The ability of various drugs to prevent the lethal effects of 4-methoxyamphetamine (PMA) and 3, 4-methylenedioxyamphetamine (MDA) were reduced by pretreatment with phentolamine and 6-hydroxydopamine suggesting that release of norepinephrine from peripheral adrenergic nerves contributed to their toxicity. Pretreatment with methysergide reduced the lethal effects of (+)- and (-)-amphetamine, MDA, PMA and 2, 5-dimethoxy-4-methylamphetamine (STP) suggesting that an action on serotonergic receptors contributed to their toxicity. Pretreatment with 4-chloroamphetamine, practolol and haloperidol did not alter the lethal effects of the agents studied.