Article

The next addiction-causing drug class 4-quinazolinone derivatives: analyses of methaqualone analogs including recently discovered 2-methoxyqualone by different modes of mass spectrometry

Authors:
To read the full-text of this research, you can request a copy directly from the authors.

Abstract

PurposeThe information on analytical methods for 4-quinazolinone recreational drugs, such as methaqualone, etaqualone and 2-methoxyqualone, is almost scant. In this study, product ion spectra of gas chromatography−tandem mass spectrometry (GC−MS/MS) with different collision energies were presented for these drugs. Because 2-methoxyqualone is a new recreational drug discovered in dubious tablets very recently, much more detailed data obtained by different types of mass spectrometry instruments, and quantification data of 2-methoxyqualone in the tablet together with its validation were demonstrated.Methods The methods for analyses were GC−MS/MS, high-resolution ultra-high-performance liquid chromatography–quadrupole time-of-flight mass spectrometry and liquid chromatography−tandem mass spectrometry.ResultsThe GC−MS/MS product ion spectra of the three compounds with different collision energies have not been reported before. They were very useful to tentatively identify unknown compounds. If a reference standard is available, the final identification and quantification can be achieved by measurements of product ion spectra and in selected reaction monitoring mode very easily by GC−MS/MS. The final identification and quantification for the new 2-methoxyqualone were performed in this way. The content of the compound was 69.8 ± 0.5% (w/w) in the tablet. Acetaminophen and caffeine coexisted in the tablet with approximate concentrations at 10 and 5%, respectively.Conclusions In this article, we have presented product ion spectra of methaqualone, etaqualone and 2-methoxyqualone at different collision energies by GC−MS/MS for the first time. In addition, this is the first paper to describe the details of quantification of 2-methoxyqualone in the authentic seized product.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

ResearchGate has not been able to resolve any citations for this publication.
Article
Full-text available
Background γ-Aminobutyric acid sub-type A receptors (GABA A Rs) are the most prominent inhibitory neurotransmitter receptors in the CNS. They are a family of ligand-gated ion channel with significant physiological and therapeutic implications. Main body GABA A Rs are heteropentamers formed from a selection of 19 subunits: six α (alpha1-6), three β (beta1-3), three γ (gamma1-3), three ρ (rho1-3), and one each of the δ (delta), ε (epsilon), π (pi), and θ (theta) which result in the production of a considerable number of receptor isoforms. Each isoform exhibits distinct pharmacological and physiological properties. However, the majority of GABA A Rs are composed of two α subunits, two β subunits, and one γ subunit arranged as γ2β2α1β2α1 counterclockwise around the center. The mature receptor has a central chloride ion channel gated by GABA neurotransmitter and modulated by a variety of different drugs. Changes in GABA synthesis or release may have a significant effect on normal brain function. Furthermore, The molecular interactions and pharmacological effects caused by drugs are extremely complex. This is due to the structural heterogeneity of the receptors, and the existence of multiple allosteric binding sites as well as a wide range of ligands that can bind to them. Notably, dysfunction of the GABAergic system contributes to the development of several diseases. Therefore, understanding the relationship between GABA A receptor deficits and CNS disorders thus has a significant impact on the discovery of disease pathogenesis and drug development. Conclusion To date, few reviews have discussed GABA A receptors in detail. Accordingly, this review aims to summarize the current understanding of the structural, physiological, and pharmacological properties of GABA A Rs, as well as shedding light on the most common associated disorders.
Article
Full-text available
Purpose In the quantitative forensic toxicological analyses using instruments, major methods to be employed are conventional matrix-matched calibration method (MMCM). However, nowadays, the needs for using the standard addition methods (SAM) are increasing. In spite of this situation, there are no reports of the guidelines for the validations of SAM. In this review, the principle, how to perform it, advantages, disadvantages, reported application data, and the details of validation procedures for the SAM are described. Methods Various databases such as SciFinder, Google and Google Scholar were utilized to collect relevant reports referring to the SAM. The long experiences of our research group on the SAM were also included in this review. Results Although the experimental procedures for the SAM are much more laborious than those of the MMCM, the SAM is essential to quantify target xenobiotic(s) in special matrices such as human solid tissues or biles, which remarkably interfere with the usual quantitative analyses. The validation methods for the SAM have been also proposed for the cases in the absence of the blank matrices. Conclusions To our knowledge, this is the first presentation of detailed SAM procedure and its validation, which will facilitate the use of the SAM in forensic toxicology. Especially for its validation, new simple methods have been proposed.
Article
Full-text available
Methylmethaqualone is a sedative designer drug created by adding a methyl group to the 3-phenyl ring of methaqualone, and is at present not subject to restrictive regulation in many countries. To our knowledge, no case of methylmethaqualone abuse has been published to date in the scientific literature, and the only sources of information are users' reports on Web discussion forums and data from preclinical animal studies. We report a case of oral methylmethaqualone abuse confirmed by liquid chromatography tandem mass spectrometry in a 24-year-old previously healthy Caucasian male. Observed symptoms and signs such as central nervous system depression alternating with excitation, psychomotor agitation, muscle hyperactivity, and tachycardia were compatible with methaqualone-induced adverse effects. Except for the mild tachycardia (115 beats/min), other vital signs were normal: blood pressure 134/89 mmHg, body temperature 36.2°C (97.16°F), and peripheral oxygen saturation 99% while breathing room air. The ECG showed no prolongation of the QT interval and the QRS duration was normal. Laboratory analysis revealed a slight increase in creatine kinase (368 U/L) and alanine aminotransferase (90 U/L) serum concentrations. Blood alcohol concentration was 0.32 g/L. Methylmethaqualone was identified in a serum sample collected on admission which was analyzed by a liquid chromatography tandem mass spectrometry toxicological screening method using turbulent flow online extraction. After a few days the patient ingested the same amount of substance with identical symptoms. Based on the chemical structure and animal data, and according to this case report and users' Web reports, methylmethaqualone appears to have a similar acute toxicity profile to methaqualone, with marked psychomotor stimulation. Symptoms of acute toxicity can be expected to resolve with supportive care.
Article
Methaqualone, known previously under the brand name Quaalude, is a Schedule I sedative hypnotic drug that may cause neurotoxicity in overdose, characterized by somnolence, hyperreflexia and muscular hyperactivity. We present a case of a 21-year-old male who reportedly ingested methaqualone in addition to insufflation of street cocaine. He subsequently developed hypoxia, hyperreflexia, myoclonus, and altered mental status. His laboratory results were notable for the presence of methemoglobinemia, which was most likely due to a cocaine contaminant. Laboratory analysis of the alleged methaqualone pills identified the substance as SL-164, a dichlorinated methaqualone analog. Urine toxicology results were positive for SL-164 (and presumed metabolites) as well as for cocaine and tetrahydrocannabinol metabolites. The patient was treated with supplemental oxygen and a benzodiazepine (lorazepam) and observed in the Emergency Department (ED) until his symptoms resolved. This case highlights current community access to methaqualone analogs. The case also focuses on laboratory techniques used to identify the methaqualone analog.
Article
In this study, sensitive analytical procedure for detection and quantification of etaqualone in human hair samples using gas chromatography tandem mass spectrometry (GC-MS/MS) was newly established, and applied it to authentic human samples obtained from an abuser. In this method, the hair samples were treated with hydrochloric acid and then extracted with ethyl ether. The ether layer was dried in a warm water bath, and the residue was reconstituted in ethyl acetate, followed by GC-MS/MS analysis. Multiple reaction monitoring (MRM) mode was used for data collection, and quantitative analysis was performed using internal standard method. Good linear relationship within the concentration range of 1-100 pg/mg were obtained in calibrators for the hair samples showing its correlation coefficient value was 0.9993. The lower limit of quantitation in this study was 1 pg/mg and the recovery rate examined ranged from 100.4% to 108.5%. The intra-day precision and accuracy were less than 5.0% and 5.8%, respectively. The inter-day precision and accuracy were lower than 6.4% and 4.6%, respectively. Using this established method, etaqualone could be detected in the hair sample obtained from a suspected user to be level of 65.2 pg/mg. It should be expected that the method established in this study would contribute to rapid detection and identification of psychotropic drug etaqualone among multiple fields including forensic investigation, clinical application and of course public health matters.
Article
Background: A 22-year-old male with a known history of drug abuse presented to our department with prolonged agitated delirium, myocloni, tachycardia and subfebrile temperature after the deliberate ingestion of opium poppy tea (Papaver somniferum L.) together with the methaqualone analog SL-164 (5-chloro-3-(4-chloro-2-methylphenyl)-2-methyl-4(3H)-quinazolinone) which is sold online as a designer drug. Methods: SL-164 and its hydroxy metabolites were detected in serum and urine via liquid chromatography-quadrupole-time-of-flight mass spectrometry (LC-QTOF-MS). Results: The pronounced delirium was treated with benzodiazepines and neuroleptics; temporary medical restraint had to be applied. Symptoms completely resolved over the next 72 h and the patient was discharged on day three able to give consent. Conclusions: Although methaqualone was a popular and widespread sedative in the 1950s and 60 s before its discontinuation in the USA in 1985, derivatives of the methaqualone class have not previously played a large role as drugs of abuse in the rapidly growing market of new psychoactive substances. To our knowledge, this is the first case of agitated delirium with detection of SL-164 and hydroxylated metabolites in a patient’s serum and urine.
Article
Mebroqualone is an analogue of methaqualone, and there is a very little published information regarding the toxicity of this designer drug. We describe two cases with non-lethal levels of mebroqualone in blood collected at autopsy. Case 1 was an accidental death that involved a house fire, and the decedent was found to have a blood mebroqualone concentration of 10,228 ng/mL. Case 2 was a completed suicide by train, and the decedent was found to have a blood concentration of 115 ng/mL. To our knowledge, this is the first report in the scientific literature to compare two postmortem blood concentrations of mebroqualone. Mebroqualone was extracted from postmortem blood using a simple liquid-liquid extraction procedure and analyzed via gas chromatography-mass spectrometry.
Article
To X o youthful drug users, the seductive white tablets represent "luding out." They promise a "high" superior to that offered by barbiturates, a drunk without the impotence or the hangover, an aphrodisiacal experience.While these properties of methaqualone—known by the US trade name Quaaludes or, in street-parlance, "ludes"—are probably largely mythical, the ill effects of methaqualone abuse are as real as the "luded" adolescents now arriving at hospital emergency rooms and at morgues in record numbers. These youngsters present with life-threatening toxicity from overdosage, fatal personal injury, or a severe withdrawal syndrome that can progress to convulsions.Methaqualone is now the leading drug of abuse next to marijuana, notes Gene Haislip, director, Office of Compliance and Regulatory Affairs, US Drug Enforcement Administration (DEA). In terms of causing injuries, he adds, the drug is now outstripping even heroin and cocaine on the illicit market in 13 major cities throughout the
Article
In the present study we have elucidated the functional characteristics and mechanism of action of methaqualone (2-methyl-3-o-tolyl-4(3H)-quinazolinone, Quaalude®), an infamous sedative-hypnotic and recreational drug from the 1960-70s. Methaqualone was demonstrated to be a positive allosteric modulator (PAM) at human α1,2,3,5β2,3γ2S GABAA receptors (GABAARs) expressed in Xenopus oocytes, whereas it displayed highly diverse functionalities at the α4,6β1,2,3δ GABAAR subtypes, ranging from inactivity (α4β1δ), through negative (α6β1δ) or positive allosteric modulation (α4β2δ, α6β2,3δ), to superagonism (α4β3δ). Methaqualone did not interact with the benzodiazepine, barbiturate or neurosteroid binding sites in the GABAAR. Instead, the compound is proposed to act through the transmembrane β((+))/α((-)) subunit interface of the receptor, possibly targeting a site overlapping with that of the general anesthetic etomidate. The negligible activities displayed by methaqualone at numerous neurotransmitter receptors and transporters in an elaborate screening for additional putative CNS targets suggest that it is a selective GABAAR modulator. The mode of action of methaqualone was further investigated in multichannel recordings from primary frontal cortex networks, where the overall activity changes induced by the compound at 1-100 μM concentrations were very similar to those mediated by other CNS depressants. Finally, the free methaqualone concentrations in mouse brain arising from doses producing significant in vivo effects in assays for locomotion and anticonvulsant activity were found to correlate fairly well with its potencies as a modulator at the recombinant GABAARs. Hence, we propose that the multifaceted functional properties exhibited by methaqualone at GABAARs give rise to its effects as a therapeutic and recreational drug. The American Society for Pharmacology and Experimental Therapeutics.
Article
We experienced an autopsy case of a 21-year-old male Caucasian, in which the direct cause of his death was judged as subarachnoid hemorrhage. There was cerebral arteriovenous malformation, which seemed related to the subarachnoid hemorrhage. The postmortem interval was estimated to be about 2days. By our drug screening test using gas chromatography-mass spectrometry, we could identify α-pyrrolidinobutiophenone (α-PBP) in his urine specimen, which led us to investigate the postmortem distribution of α-PBP in this deceased. The specimens dealt with were right heart blood, left heart blood, femoral vein blood, cerebrospinal fluid, urine, stomach contents and five solid tissues. The extraction of α-PBP and α-pyrrolidinovalerophenone (α-PVP, internal standard) was performed by a modified QuEChERS (quick, easy, cheap, effective, rugged and safe) method, followed by the analysis by liquid chromatography-tandem mass spectrometry. Because this study included various kinds of human matrices, we used the standard addition method to overcome the matrix effects. The highest concentration was found in urine, followed by stomach contents, the kidney, lung, spleen, pancreas and liver. The blood concentrations were about halves of those of the solid tissues. The high concentrations of α-PBP in urine and the kidney suggest that the drug tends to be rapidly excreted into urine via the kidney after its absorption into the blood stream. The urine specimen is of the best choice for analysis. This is the first report describing the postmortem distribution of α-PBP in a human to our knowledge.
Article
A validated gas chromatographic–mass spectrometric method for quantitative analysis of methaqualone (MTQ) in illicit preparations is reported. The method proved to have a coefficient of variation of below 5%. Four batches of seized tablets, two pairs with similar imprints, were analyzed. It was found that the average MTQ concentration in all four batches of tablets differed significantly (p=0.01) rendering it impossible to conclude that, on the basis of MTQ concentration alone, the batches with a similar logo originated from the same manufacturer or manufacturing batch. Conversely, it can be said that in this case, the four batches originated from either different clandestine laboratories or manufacturing batches.
Article
In 1972 methaqualone emerged as a major drug of nonmedical use in the United States--a subject of widespread publicity and public concern. In late 1973, government officials responded by taking the unprecedented measure of imposing the strictest controls available under United States law on a drug which had previously been subject only to a simple prescription requirement. Methaqualone had a similar history in other countries, particularly in Germany, Japan, and Great Britain. However, this history was ignored by United States officials until nonmedical methaqualone use had become a substantial problem in the United States.
Article
Of 246 methaqualone-related deaths identified during an 11-year period (1971 through 1981), 76% have occurred since 1977 and 72% have involved fatal trauma. One third of the victims died in vehicular crashes. Sharp increases in methaqualone-related traumatic suicides, nonvehicular accidents, and homicides have occurred since 1978. This report discusses demographic and toxicological findings, particularly in regard to counterfeit methaqualone. The pattern of fatal methaqualone abuse has changed from an overdose phenomenon in the early 1970s to one of traumatic death. Victims frequently have exhibited poor judgment, impulsive behavior, and somnolence while attempting to function in their environment. The socioeconomic impact of recreational methaqualone abuse should be curtailed by appropriate governmental action and restraint in the prescribing of methaqualone. (JAMA 1983;249:621-626)
Article
Reliable analytical data are a prerequisite for correct interpretation of toxicological findings in the evaluation of scientific studies, as well as in daily routine work. Unreliable analytical data might not only be contested in court, but could also lead to unjustified legal consequences for the defendant or to wrong treatment of the patient. Therefore, new analytical methods to be used in forensic and/or clinical toxicology require careful method development and thorough validation of the final method. This is especially true in the context of quality management and accreditation, which have become matters of increasing relevance in analytical toxicology in recent years. In this paper, important considerations in analytical method validation will be discussed which may be used as guidance by scientists wishing to develop and validate analytical methods.
Methaqualone abuse, the quiet epidemic
  • E F Pascarelli
Pascarelli EF (1973) Methaqualone abuse, the quiet epidemic. JAMA 224:1512-1514. https:// doi. org/ 10. 1001/ jama. 1973. 03220 25003 4011
Identification and estimation of methaqualone in toffee samples using gas chromatography-mass spectrometry, Fourier transform infrared spectrometry, and high-performance thin-layer chromatography
  • D K Kuila
  • B Muhkopadhyay
  • S C Lahiri
Kuila DK, Muhkopadhyay B, Lahiri SC (2006) Identification and estimation of methaqualone in toffee samples using gas chromatography-mass spectrometry, Fourier transform infrared spectrometry, and high-performance thin-layer chromatography. Forensic Sci Commun. https:// archi ves. fbi. gov/ archi ves/ about-us/ lab/ foren sic-scien ce-commu nicat ions/ fsc/ oct20 06/ resea rch/ 2006_ 10_ resea rch02. htm Accessed May 2022