Non-conserved residues dictate dopamine transporter selectivity for the potent synthetic cathinone and psychostimulant MDPV

Steele, Tyler W.E.; Spires, Zachary; Jones, Charles B.; Glennon, Richard A.; Dukat, Małgorzata; Eltit, José M.

doi:10.1016/j.neuropharm.2021.108820

Cited by 7 publications

(5 citation statements)

References 42 publications

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“…Within the realm of psychedelic therapeutics, understanding the interaction of compounds with the DAT assumes paramount significance, given the central role of dopamine in both physiological and psychological processes as well as its pivotal role in substance addiction. 27 As we embark on this scientific journey, we will elucidate the molecular and pharmacological insights brought to light by the DAT QSAR model. These insights hold the potential to not only enhance the efficacy of existing compounds but also pave the way for the development of novel drugs with improved safety profiles.…”

Section: Resultsmentioning

confidence: 99%

“…In the pursuit of unraveling the intricate relationships between chemical compounds and biological systems, our exploration now delves into the specific insights derived from our QSAR model for the inhibition of the DAT. Within the realm of psychedelic therapeutics, understanding the interaction of compounds with the DAT assumes paramount significance, given the central role of dopamine in both physiological and psychological processes as well as its pivotal role in substance addiction . As we embark on this scientific journey, we will elucidate the molecular and pharmacological insights brought to light by the DAT QSAR model.…”

Section: Resultsmentioning

confidence: 99%

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Uncovering Structure–Activity Relationships of Phenethylamines: Paving the Way for Innovative Mental Health Treatments

Karabulut,

Kaur,

Gauld

2024

ACS Chem. Neurosci.

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The rapidly evolving psychedelic industry has garnered considerable attention due to 3,4-methylenedioxymethamphetamine-assisted psychotherapy's ground-breaking success in treating moderate-to-severe Post-traumatic Stress Disorder in two Phase 3 clinical trials. This has opened Pandora's box for the development of innovative therapeutic modalities. Of particular interest are the phenethylamines and their ability to inhibit monoamine transporters. In this study, we employed the quantitative structure− activity relationship methodology to develop three vigorous models for the reuptake of serotonin, dopamine, and norepinephrine through monoamine transporters. These models were thoroughly validated using various criteria, including fitting (R 2 DAT = 0.869, R 2 SERT = 0.828, and R 2 NET = 0.887), internal (Q 2 loo DAT = 0.795, Q 2 loo SERT = 0.784, and Q 2 loo NET = 0.820), and external (RMSEext DAT = 0.373, R 2 ext DAT = 0.831, RMSEext SERT = 0.200, R 2 ext SERT = 0.955, RMSEext NET = 0.318, and R 2 ext NET = 0.711) criteria.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Uncovering Structure–Activity Relationships of Phenethylamines: Paving the Way for Innovative Mental Health Treatments

Karabulut,

Kaur,

Gauld

2024

ACS Chem. Neurosci.

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“…Analysis at hDAT revealed that supportive hydrophobic and acid/base interplays from amino acid residues PHE326, VAL328, SER149, MET427, SER422, ALA423, GLY426, ASN157, GLY153, and VAL152 were involved in the positive interactions associated with the substituents. Two of these residues, SER149 and GLY153, have been shown to be important in ligand recognition through mutagenesis studies . Unsubstituted 1a is likely less potent than the 3,4-dichloro 1b due to an absence of the favorable hydrophobic and electrostatic interactions associated with the substituents on the aromatic moiety.…”

Section: Resultsmentioning

confidence: 99%

“…Two of these residues, SER149 and GLY153, have been shown to be important in ligand recognition through mutagenesis studies. 12 Unsubstituted 1a is likely less potent than the 3,4-dichloro 1b due to an absence of the favorable hydrophobic and electrostatic interactions associated with the substituents on the aromatic moiety. Halogen bond formation between 1b and the hydroxyl group of SER149 is indicated by HINT analysis as a base−base clash with a negative score (Note: HINT does not recognize the σ-hole on a Cl atom with a δ + charge); whether this formation takes place in vitro is unknown.…”

Section: ■ Introductionmentioning

confidence: 99%

Do 2-(Benzoyl)piperidines Represent a Novel Class of hDAT Reuptake Inhibitors?

Jones

Eltit

Dukat

2023

ACS Chem. Neurosci.

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2-(Benzoyl)piperidines (analogues of 1a), structural hybrids of the clinically employed ADHD medication methylphenidate (2) and the abused synthetic cathinone pentedrone (3), have been previously reported to act as novel and selective reuptake inhibitors of the human dopamine transporter (hDAT). One of the more potent benzoylpiperidines, as is the case with methylphenidate analogues, is its 3,4-dichloroaryl counterpart. Here, we demonstrate using homology models that these compounds (i.e., benzoylpiperidines and methylphenidate analogues) likely bind in a comparable manner at hDAT. In addition, it is shown here that the 3,4-dichlorobenzoylpiperidine analogue of 1a is more potent than its 3,4-dimethyl counterpart, suggesting that the electronic character of the substituents might play a role in the potency of these hybrids. Furthermore, the 3,4-benz-fused (i.e., naphthyl) benzoylpiperidine analogue acts in the same manner as its corresponding methylphenidate counterpart at hDAT. As with its methylphenidate counterpart, the naphthyl compound also acts, rather uniquely (although with lower potency) relative to other members of the two series, at the human serotonin transporter (hSERT). In conclusion, the benzoylpiperidines represent a novel structural class of hDAT reuptake inhibitors that function in a manner similar to their methylphenidate counterparts.

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“…2.2 5-HT 2B receptor functional activity using Ca 2+ mobilization assay A stable cell line was generated expressing the human 5-HT 2B receptor using the Flp-In T-REx system (Thermo Fisher) (Younkin et al, 2016;Steele et al, 2021). Briefly, 5-HT 2B receptor coding plasmid was obtained from cDNA Resource Center (cat # HTR02B0000).…”

Section: Methodsmentioning

confidence: 99%

Binding and functional structure-activity similarities of 4-substituted 2,5-dimethoxyphenyl isopropylamine analogues at 5-HT2A and 5-HT2B serotonin receptors

et al. 2023

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Certain 4-substituted analogs of 1-(2,5-dimethoxyphenyl)isopropylamine (2,5-DMA) are psychoactive classical hallucinogens or serotonergic psychedelic agents that function as human 5-HT2A (h5-HT2A) serotonin receptor agonists. Activation of a related receptor population, h5-HT2B receptors, has been demonstrated to result in adverse effects including cardiac valvulopathy. We previously published on the binding of several such agents at the two receptor subtypes. We hypothesized that, due to their structural similarity, the 5-HT2A and 5-HT2B receptor affinities of these agents might be related, and that QSAR studies might aid future studies. For a series of 13 compounds, it is demonstrated here that i) their published rat brain 5-HT2 receptor affinities are significantly correlated with their h5-HT2A (r = 0.942) and h5-HT2B (r = 0.916) affinities, ii) as with r5-HT2 receptor affinity, h5-HT2A affinity is correlated with the lipophilicity of the 4-position substituent (r = 0.798), iii) that eight of the ten compounds examined in functional (Ca+2 mobilization in stable cell lines generated expressing the human 5-HT2B receptor using the Flp-In T-REx system) assays acted as h5-HT2B agonists (4-substituent = H, F, Br, I, OCH2CH3, NO2, nC3H7, tC4H9) and two (n-hexyl and benzyl) as antagonists, iv) h5-HT2B affinity but not action was correlated with the lipophilicity of the 4-position substituent (r = 0.750; n = 10). The findings suggest that h5-HT2B receptor affinity, and its relationship to substituent lipophilicity, might be approximated by rat and h5-HT2A affinity but cannot be used as a predictor of h5-HT2B agonist action of 2,5-DMA analogs. Furthermore, given that certain 2,5-DMA analogs are on the clandestine market, their potential to produce cardiac side effects following persistent or chronic use via activation of h5-HT2B receptors should be considered.

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Non-conserved residues dictate dopamine transporter selectivity for the potent synthetic cathinone and psychostimulant MDPV

Cited by 7 publications

References 42 publications

Uncovering Structure–Activity Relationships of Phenethylamines: Paving the Way for Innovative Mental Health Treatments

Uncovering Structure–Activity Relationships of Phenethylamines: Paving the Way for Innovative Mental Health Treatments

Do 2-(Benzoyl)piperidines Represent a Novel Class of hDAT Reuptake Inhibitors?

Binding and functional structure-activity similarities of 4-substituted 2,5-dimethoxyphenyl isopropylamine analogues at 5-HT2A and 5-HT2B serotonin receptors

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