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Inhibitors of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Wu et al. (1997) have investigated the inhibitory effect of 15 amphetamine analogs (Figure 4.13) on dextromethorphan O-demethylation in human liver microsomes. The authors have found that the presence of a methylenedioxy group in the 3,4-positions of both amphetamine (Ki = 26.5 μM) and methamphetamine (Ki= 25 μM) increases the affinity for CYP2D6 to 1.8 and 0.6 μM, respectively. Addition of a methoxy group to amphetamine in the 2-position also increases the affinity for CYP2D6 (Ki =11.5 μM) (Wu et al. 1997). The compound with the highest affinity for CYP2D6 is an amphetamine analog, MMDA-2, containing both a methoxy group in the 2-position and a methylenedioxy group (Ki = 0.17 μM). MDMA is also a potent competitive inhibitor of CYP2D6 in human liver microsomes (Wu et al. 1997). Mescaline does not inhibit CYP2D6. Since many amphetamine analogs are metabolized by CYP2D6, they may inhibit their own metabolism and thus cause accumulation of the drugs in the body.
Stimulants
Published in David J. George, Poisons, 2017
Methylenedioxy-methamphetamine (MDMA) is a popular stimulant because it can impart a general sense of well-being, increase emotional warmth and sensory perception, and enhance empathy toward others. There appears to be a general belief that, compared to other abused drugs, MDMA is a relatively safe drug for occasional use. In reality, MDMA can produce a variety of adverse effects that include hypertension, panic attacks, coma, and seizures. In some circumstances, MDMA can produce life-threatening hyperthermia and kidney failure. Sudden deaths can occur in MDMA users from cardiac arrhythmias. This possibility is greater for individuals with preexisting cardiovascular disorders. Users commonly ascribe toxic effects of MDMA to lack of purity or a bad batch of illegal MDMA, but most of the products distributed as MDMA (Ecstasy, Molly) are knowingly manufactured with substances other than MDMA and generally are significantly more toxic.
Medical Consequences of the Use of Hallucinogens: LSD, Mescaline, PCP, and MDMA (“Ecstasy”)
Published in John Brick, Handbook of the Medical Consequences of Alcohol and Drug Abuse, 2012
Timothy Wiegand, Dung Thai, Neal Benowitz
MDMA is a ring-substituted amphetamine derivative. In its pure form, it is a white crystalline powder. MDMA is similar in structure to methamphetamine with the addition of the methylenedioxy (-O-CH2-O-) group attached to positions 3 and 4 of the aromatic ring of the methamphetamine molecule. MDMA exists as two enantiomers, both the R and S (d- and l-) forms. It has been suggested that the S enantiomer contributes to “amphetamine-like” effects while the R enantiomer gives more hallucinogenic and empathogenic qualities to the experience. These suggestions are based on dose-response curves for changes in serotonergic and other monoamine functions. In vitro studies indicate that MDMA releases CNS monoamine neurotransmitters via “calcium-independent release” while also inhibiting the reuptake of monoamines: dopamine, norepinephrine and, particularly, serotonin (5-HT). Despite this effect on multiple neurotransmitter systems the centrally mediated hallucinogenic or empathogenic effects are thought to be mediated mainly by altered 5-HT neurotransmission (Kalant, 2001; Shulgin, 1986). Compared with the hallucinogenic phenethylamine, mescaline, and LSD which exert their effects on the postsynaptic 5-HT receptors, MDMA causes presynaptic release of 5-HT while also inhibiting its reuptake. Radioisotope studies have shown that MDMA may enter the presynaptic terminal via the same receptor that selective serotonin reuptake inhibitors (SSRIs) block. Accordingly, there are case reports in which patients have had the effects of MDMA attenuated while taking SSRIs (Liechti et al., 2000).
LC-MS/MS based detection and characterization of covalent glutathione modifications formed by reactive drug of abuse metabolites
Published in Xenobiotica, 2019
R. Allen Gilliland, Carolina Möller, Anthony P. DeCaprio
Formation of MDPV2 is associated with loss of the methylene bridge and pyrrolidine moiety (via oxidative deamination) in addition to rearomatization, while MDPV3 may form via the same process in addition to a hydroxylation on the resultant alkyl chain. Demethylenation, common to either the orthocatechol or orthoquinone, and oxidative deamination of methylenedioxy type drugs has been reported in the literature (Meyer & Maurer, 2010; Yamada et al., 2005). The orthoquinone formed by some methylenedioxy drugs has been reported to be the reactive metabolite responsible for toxicity (Kalgutkar et al., 2005). As mentioned previously, some of the drugs underwent a rearomatization step following GSH adduction and NIH shift (CLZ1, MDPV1, MDPV2, NAL1, OXY1, THC1 and THC2) while others did not (DZP1 and NAL2). This observation is similar to what has been generally reported in the literature involving NIH shifts (Guengerich, 2003).
Acute poisonings in Croatia: differences in epidemiology, associated comorbidities and final outcomes – a single-centre 15-year follow-up
Published in Clinical Toxicology, 2019
Iva Klobučar, Ines Potočnjak, Jelena Dumančić, Karlo Stemberger, Miriam Čupić, Tomislav Kokotović, Zdravka Kucijan, Vesna Degoricija
Blood samples were taken for standard laboratory analyses, including complete blood count (COULTER® LH 750 Hematology Analyzer [Beckman Coulter, Miami, Florida, USA] in 2001 and 2010; UniCel® DxH™ 800 Coulter® Cellular Analysis System [Beckman Coulter, Brea, California, USA] in 2015) and biochemistry tests (Olympus AU2700 [Olympus Optical Co. Ltd., Tokyo, Japan] in 2001 and 2010; ARCHITECT c8000 [Abbott Laboratories, Abbott Park, Chicago, Illinois, USA] in 2015), with the addition of the suspected substance or its metabolite concentration measurement in blood or urine (serum ethanol – quantitative test – Abbott AxSYM Immunoassay Analyzer [Abbott Laboratories, Abbott Park, Chicago, Illinois, USA] in 2001 and 2010, ARCHITECT c8000 [Abbott Laboratories, Abbott Park, Chicago, Illinois, USA] in 2015; benzodiazepines, barbiturates, heroin, methadone, cannabis, cocaine, amphetamine, methamphetamine and 3,4-methylenedioxy-methamphetamine (MDMA) in urine – qualitative dipstick screening test – DOA MultiGnost® 10 [BioGnost d.o.o., Zagreb, Croatia]). Chromatography and mass spectrometry for the confirmation of urine dipstick test results and self-reports about gamma hydroxybutyrate (GHB), 4-bromo-2,5-dimethoxyphenylamine (2C-B) and synthetic cannabinoids (Galaxy) intake were not available.
The synthetic cathinone α-pyrrolidinovalerophenone (α-PVP): pharmacokinetic and pharmacodynamic clinical and forensic aspects
Published in Drug Metabolism Reviews, 2018
Leandro Nóbrega, Ricardo Jorge Dinis-Oliveira
Cathinone is a monoamine and the main psychoactive naturally occurring alkaloid found in the leaves of the Catha edulis plant, commonly known as khat (Marinetti and Antonides 2013; Watterson and Olive 2014). SC are phenylalkylamines cathinone analogs, and are often termed ‘bk-amphetamines’ or ‘β-keto amphetamines’ due to the presence of beta-ketone group at the β-position of the side chain (Prosser and Nelson 2012; Miller et al. 2017; Valento and Lebin 2017). Functional group substitutions to the core structure of the parent cathinone compound (Figure 1) have yielded a large number of SC on the street and cyber drug markets, which can be separated into four different chemical families based on the substitutions made (Figure 2) (Valente et al. 2014; Miller et al. 2017): (i) the most basic N-alkylated derivatives, which may present alkyl substitutions in the α-carbon of the side chain (e.g. 4-methy-lethcathinone) and/or in the benzyl ring (e.g. mephedrone); (ii) the methylenedioxy benzyl ring derivatives (e.g. methylone), which are structurally similar to 3,4-methylenedioxyamphetamines (e.g. ecstasy or MDMA); (iii) the N-pyrrolidine derivatives (e.g. α-PVP) and; (iv) the synthetic cathinone family that has both the 3,4-methylenedioxy ring substitution and the N-pyrrolidinyl moiety (e.g. 3,4-methylenedioxy-α-pyrrolidinovalerophenone or 3,4-methylenedioxypyrovalerone or MDPV). Many of these derivatives suffer only slight changes to their structure aiming to bypass the legislation regarding NPS. In the US and Europe, bupropion is the only SC that has a medical application for treatment of depression and smoking-cessation aid (Miller et al. 2017).