Ethylenedioxy homologs of N -methyl-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA) and its corresponding cathinone analog methylenedioxymethcathinone: Interactions with transporters for serotonin, dopamine, and norepinephrine

Bello, Fabio Del; Sakloth, Farhana; Partilla, John S.; Baumann, Michael H.; Glennon, Richard A.

doi:10.1016/j.bmc.2015.07.035

Cited by 6 publications

(6 citation statements)

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“…In addition, the increase in chain length (change of methylenedioxy from MDMC to ethylendioxy, specific for EDMC) decreases the ability of substances to cause the release of the three mediators [ 51 ].…”

Section: Resultsmentioning

confidence: 99%

Psychoactive Drugs—From Chemical Structure to Oxidative Stress Related to Dopaminergic Neurotransmission. A Review

et al. 2021

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Nowadays, more and more young people want to experience illegal, psychoactive substances, without knowing the risks of exposure. Besides affecting social life, psychoactive substances also have an important effect on consumer health. We summarized and analyzed the published literature data with reference to the mechanism of free radical generation and the link between chemical structure and oxidative stress related to dopaminergic neurotransmission. This review presents data on the physicochemical properties, on the ability to cross the blood brain barrier, the chemical structure activity relationship (SAR), and possible mechanisms by which neuronal injuries occur due to oxidative stress as a result of drug abuse such as “bath salts”, amphetamines, or cocaine. The mechanisms of action of ingested compounds or their metabolites involve intermediate steps in which free radicals are generated. The brain is strongly affected by the consumption of such substances, facilitating the induction of neurodegenerative diseases. It can be concluded that neurotoxicity is associated with drug abuse. Dependence and oxidative stress are linked to inhibition of neurogenesis and the onset of neuronal death. Understanding the pathological mechanisms following oxidative attack can be a starting point in the development of new therapeutic targets.

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Section: Resultsmentioning

confidence: 99%

Psychoactive Drugs—From Chemical Structure to Oxidative Stress Related to Dopaminergic Neurotransmission. A Review

et al. 2021

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“…Expansion of the methylenedioxy ring of methylone ( 24 ) to an ethylenedioxy ring (i.e., ethylenedioxymethcathinone, EDMC; 30 ; Figure 7) decreased its potency as a releasing agent at all three transporters by 2- to 3-fold (Del Bello et al, 2015). Homolgation of the α-methyl group of methylone ( 24 ) to an α-ethyl group (i.e., butylone; 31 ) and replacement of the methylenedioxy group of MDPV ( 27 ) with a fused phenyl ring (i.e., naphyrone; 32 ) resulted in reuptake inhibitors at the three transporters (Simmler et al, 2013; Eshleman et al, 2013).…”

Section: Current Sar Studiesmentioning

confidence: 99%

Structure-Activity Relationships of Synthetic Cathinones

Glennon

Dukat

2016

Current Topics in Behavioral Neurosciences

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Until recently, there was rather little interest in the structure-activity relationships (SARs) of cathinone analogs because so few agents were available, and because they represented a relatively minor drug abuse problem. Most of the early SAR was formulated on the basis of behavioral (e.g. locomotor and drug discrimination) studies using rodents. With the emergence on the clandestine market in the last few years of a large number of new cathinone analogs, termed “synthetic cathinones”, and the realization that they likely act at dopamine, norepinephrine, and/or serotonin transporters as releasing agents (i.e., as substrates) or reuptake inhibitors (i.e., as transport blockers), it has now become possible to better examine their SAR, and even their quantitative SAR (QSAR), in a more effective and systematic manner. An SAR picture is beginning to emerge and key structural features, such as the nature of the terminal amine, the size of the α substituent, stereochemistry, and the presence and position of aromatic substituents, are being found to impact action (i.e., as releasing agents or reuptake inhibitors) and transporter selectivity.

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“…3,4-Methylenedioxymethamphetamine (MDMA, “ecstasy”) is a popular drug of abuse which exerts stimulant and entactogenic effects by evoking release and inhibiting uptake of presynaptic norepinephrine, 5-HT and dopamine (Del Bello et al, 2015; Rickli et al, 2015a). The enzymatic biotransformation of MDMA includes two main pathways: (1) N -demethylation to form 3,4-methylenedioxyamphetamine (MDA) and (2) O -demethylenation to form catechol metabolites 3,4-dihydroxymethamphetamine (HHMA) and 3,4-dihydroxyamphetamine (HHA) (de la Torre et al, 2004; Kreth et al, 2000; Meyer et al, 2008; Segura et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Metabolites of the ring-substituted stimulants MDMA, methylone and MDPV differentially affect human monoaminergic systems

et al. 2019

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Background: Amphetamine analogs with a 3,4-methylenedioxy ring-substitution are among the most popular illicit drugs of abuse, exerting stimulant and entactogenic effects. Enzymatic N-demethylation or opening of the 3,4-methylenedioxy ring via O-demethylenation gives rise to metabolites that may be pharmacologically active. Indeed, previous studies in rats show that specific metabolites of 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxymethcathinone (methylone) and 3,4-methylenedioxypyrovalerone (MDPV) can interact with monoaminergic systems. Aim: Interactions of metabolites of MDMA, methylone and MDPV with human monoaminergic systems were assessed. Methods: The ability of parent drugs and their metabolites to inhibit uptake of tritiated norepinephrine, dopamine and serotonin (5-HT) was assessed in human embryonic kidney 293 cells transfected with human monoamine transporters. Binding affinities and functional activity at monoamine transporters and various receptor subtypes were also determined. Results: MDMA and methylone displayed greater potency to inhibit norepinephrine uptake as compared to their effects on dopamine and 5-HT uptake. N-demethylation of MDMA failed to alter uptake inhibition profiles, whereas N-demethylation of methylone decreased overall transporter inhibition potencies. O-demethylenation of MDMA, methylone and MDPV resulted in catechol metabolites that maintained norepinephrine and dopamine uptake inhibition potencies, but markedly reduced activity at 5-HT uptake. O-methylation of the catechol metabolites significantly decreased norepinephrine uptake inhibition, resulting in metabolites lacking significant stimulant properties. Conclusions: Several metabolites of MDMA, methylone and MDPV interact with human transporters and receptors at pharmacologically relevant concentrations. In particular, N-demethylated metabolites of MDMA and methylone circulate in unconjugated form and could contribute to the in vivo activity of the parent compounds in human users.

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Ethylenedioxy homologs of N -methyl-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA) and its corresponding cathinone analog methylenedioxymethcathinone: Interactions with transporters for serotonin, dopamine, and norepinephrine

Cited by 6 publications

References 20 publications

Psychoactive Drugs—From Chemical Structure to Oxidative Stress Related to Dopaminergic Neurotransmission. A Review

Psychoactive Drugs—From Chemical Structure to Oxidative Stress Related to Dopaminergic Neurotransmission. A Review

Structure-Activity Relationships of Synthetic Cathinones

Metabolites of the ring-substituted stimulants MDMA, methylone and MDPV differentially affect human monoaminergic systems

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