Differential effects of psychoactive substances on human wildtype and polymorphic T356M dopamine transporters (DAT)

Zwartsen, Anne; Litjens, Carlijn H C; Hondebrink, Laura; Heuvel, Jeroen J. M. W. van den; Greupink, Rick; Rüssel, Frans G. M.; Lange, Dylan W. de; Legler, Juliette; Koenderink, Jan B.; Westerink, Remco H.S.

doi:10.1016/j.tox.2019.04.012

Cited by 5 publications

(4 citation statements)

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“…A novel potentially functional SNP within the DAT1 has been described in recent research. However, the SNP showed no significant alteration in the inhibition of DA uptake by MDMA in human embryonic kidney 293 cells (63). We have also not tested for rare haplotypes because a haplotype approach may lead to very small groups and more potential statistical artifacts.…”

Section: Discussionmentioning

confidence: 98%

No Influence of Dopamine System Gene Variations on Acute Effects of MDMA

Vizeli

Liechti

2019

Front. Psychiatry

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3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is a recreational substance also investigated as medication for posttraumatic stress disorder. Dopamine (DA) system stimulation likely contributes to the acute mood effects of amphetamines, including MDMA. Genetic variants, such as single-nucleotide polymorphisms (SNPs), and polymorphic regions of the DA system genes may in part explain interindividual differences in the acute responses to MDMA in humans. We characterized the effects of common genetic variants within genes coding for key players in the DA system including the dopamine D2 receptor (DRD2/ANKK1 rs1800497, DRD2 rs6277, and rs107959), the dopamine transporter (DAT1 rs28363170, rs3836790, rs6347, rs11133767, rs11564774, rs460000, and rs463379), and dopamine D4 receptor [DRD4, variable-number tandem repeat (VNTR)] on the subjective and autonomic response to MDMA (125 mg) in pooled data from randomized, placebo-controlled, crossover studies in a total of 149 healthy subjects. Plasma concentrations of MDMA were used as covariate in the analysis to control for individual pharmacokinetic (metabolic and weight) differences. None of the tested genetic polymorphisms within the DA system altered effects of MDMA when adjusting for multiple comparisons. Genetic variations in genes coding for players of the DA system are unlikely to explain interindividual variations in the acute effects of MDMA in humans.

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Section: Discussionmentioning

confidence: 98%

No Influence of Dopamine System Gene Variations on Acute Effects of MDMA

Vizeli

Liechti

2019

Front. Psychiatry

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“…On the other hand, missense mutations have direct effects on the structure and function of transporters. Specifically, missense mutations can lead to misfolding, change in protein conformation, alter the membrane potential and sodium sensitivity, − and reduce the binding affinity of compounds, − thereby disrupting the efflux or influx. Taking DAT as an example, the D421N mutation has the ability to decrease the binding affinity and uptake activity of the substrate and also impairs the binding of ions .…”

Section: Structure and Function Of Slcsmentioning

confidence: 99%

Computational Chemistry in Structure-Based Solute Carrier Transporter Drug Design: Recent Advances and Future Perspectives

Tu,

Fu,

Zheng

et al. 2024

J. Chem. Inf. Model.

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Solute carrier transporters (SLCs) are a class of important transmembrane proteins that are involved in the transportation of diverse solute ions and small molecules into cells. There are approximately 450 SLCs within the human body, and more than a quarter of them are emerging as attractive therapeutic targets for multiple complex diseases, e.g., depression, cancer, and diabetes. However, only 44 unique transporters (∼9.8% of the SLC superfamily) with 3D structures and specific binding sites have been reported. To design innovative and effective drugs targeting diverse SLCs, there are a number of obstacles that need to be overcome. However, computational chemistry, including physics-based molecular modeling and machine learning-and deep learning-based artificial intelligence (AI), provides an alternative and complementary way to the classical drug discovery approach. Here, we present a comprehensive overview on recent advances and existing challenges of the computational techniques in structure-based drug design of SLCs from three main aspects: (i) characterizing multiple conformations of the proteins during the functional process of transportation, (ii) identifying druggability sites especially the cryptic allosteric ones on the transporters for substrates and drugs binding, and (iii) discovering diverse small molecules or synthetic protein binders targeting the binding sites. This work is expected to provide guidelines for a deep understanding of the structure and function of the SLC superfamily to facilitate rational design of novel modulators of the transporters with the aid of state-of-the-art computational chemistry technologies including artificial intelligence.

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“…There are many possible reasons for these discrepancies, ranging from the different cell types used, to the fact that not all studies used radio-labeled neurotransmitters. The fact that different cell types can give significantly different results was pointed out in a study that found that hDAT inhibition of [ 3 H]DA uptake was significantly different in wild-type compared with T356 single nucleotide polymorphism hDAT ( Zwartsen et al, 2019 ). This polymorphism has been observed in humans ( Neale et al, 2012 ), and has been shown to impede the functionality of DAT ( Herborg et al, 2018 ).…”

Section: Other Potential Substitutesmentioning

confidence: 99%

Beyond ecstasy: Alternative entactogens to 3,4-methylenedioxymethamphetamine with potential applications in psychotherapy

Oeri

2020

J Psychopharmacol

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The last two decades have seen a revival of interest in the entactogen 3,4-methylenedioxy-N-methylamphetamine (MDMA) as an adjunct to psychotherapy, particularly for the treatment of post-traumatic stress disorder. While clinical results are highly promising, and MDMA is expected to be approved as a treatment in the near future, it is currently the only compound in its class of action that is being actively investigated as a medicine. This lack of alternatives to MDMA may prove detrimental to patients who do not respond well to the particular mechanism of action of MDMA or whose treatment calls for a modification of MDMA’s effects. For instance, patients with existing cardiovascular conditions or with a prolonged history of stimulant drug use may not fit into the current model of MDMA-assisted psychotherapy, and could benefit from alternative drugs. This review examines the existing literature on a host of entactogenic drugs, which may prove to be useful alternatives in the future, paying particularly close attention to any neurotoxic risks, neuropharmacological mechanism of action and entactogenic commonalities with MDMA. The substances examined derive from the 1,3-benzodioxole, cathinone, benzofuran, aminoindane, indole and amphetamine classes. Several compounds from these classes are identified as potential alternatives to MDMA.

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Differential effects of psychoactive substances on human wildtype and polymorphic T356M dopamine transporters (DAT)

Cited by 5 publications

References 50 publications

No Influence of Dopamine System Gene Variations on Acute Effects of MDMA

No Influence of Dopamine System Gene Variations on Acute Effects of MDMA

Computational Chemistry in Structure-Based Solute Carrier Transporter Drug Design: Recent Advances and Future Perspectives

Beyond ecstasy: Alternative entactogens to 3,4-methylenedioxymethamphetamine with potential applications in psychotherapy

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