Role of amino terminal substitutions in the pharmacological, rewarding and psychostimulant profiles of novel synthetic cathinones

Duart-Castells, Leticia; Nadal-Gratacós, Núria; Muralter, Magdalena; Puster, Brigitte; Berzosa, Xavier; Estrada‐Tejedor, Roger; Niello, Marco; Bhat, Shreyas; Piccoli, David A.; Camarasa, Jorge; Sitte, Harald H.; Escubedo, Elena; López-Arnau, Raúl

doi:10.1016/j.neuropharm.2021.108475

Cited by 25 publications

(36 citation statements)

References 62 publications

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“…The HLA was video-monitored for 1 h using a specific tracking software program (Smart 3.0, Panlab, Spain), and the total traveled distance (in cm) was measured. The doses were chosen according to the psychostimulant effect induced by pentedrone and NEPD in previous studies ( Duart-Castells et al, 2021 ). Human doses of pentedrone are reported to be variable.…”

Section: Methodsmentioning

confidence: 99%

“…mechanism of action, synthetic cathinones are able to competitively inhibit dopamine (DA) and serotonin (5-HT) uptake (López-Arnau et al, 2012;Simmler et al, 2014;Duart-Castells et al, 2021); for a review, see Riley et al (2020). However, it has been demonstrated that pentylone has hybrid activity, acting as a DA transporter (DAT) blocker but a 5-HT transporter (SERT) substrate (Saha et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, some intoxications and even fatalities associated with pentylone, 4-MPD, NEP, N-ethyl-pentedrone (NEPD), and 4-methyl-ethylaminopentedrone (4-MeAP) use have been recently reported ( Fujita et al, 2015 ; Varma et al, 2017 ; Majchrzak et al, 2018 ; Zaami et al, 2018 ; Benedicte et al, 2020 ; Giachetti et al, 2020 ; Lau et al, 2020 ; Weng et al, 2020 ; Cartiser et al, 2021 ). Regarding the mechanism of action, synthetic cathinones are able to competitively inhibit dopamine (DA) and serotonin (5-HT) uptake ( López-Arnau et al, 2012 ; Simmler et al, 2014 ; Duart-Castells et al, 2021 ); for a review, see Riley et al (2020 ). However, it has been demonstrated that pentylone has hybrid activity, acting as a DA transporter (DAT) blocker but a 5-HT transporter (SERT) substrate ( Saha et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

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Structure–Activity Relationship of Novel Second-Generation Synthetic Cathinones: Mechanism of Action, Locomotion, Reward, and Immediate-Early Genes

Nadal-Gratacós

Alberto-Silva²,

Rodríguez-Soler

et al. 2021

Front. Pharmacol.

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Several new synthetic cathinones, which mimic the effect of classical psychostimulants such as cocaine or MDMA, have appeared in the global illicit drug market in the last decades. In fact, the illicit drug market is continually evolving by constantly adding small modifications to the common chemical structure of synthetic cathinones. Thus, the aim of this study was to investigate the in vitro and in vivo structure–activity relationship (SAR) of six novel synthetic cathinones currently popular as recreational drugs, pentedrone, pentylone, N-ethyl-pentedrone (NEPD), N-ethyl-pentylone (NEP), 4-methyl-pentedrone (4-MPD), and 4-methyl-ethylaminopentedrone (4-MeAP), which structurally differ in the absence or presence of different aromatic substituents and in their amino terminal group. Human embryonic kidney (HEK293) cells expressing the human isoforms of SERT and DAT were used for the uptake inhibition and release assays. Moreover, Swiss CD-1 mice were used to investigate the psychostimulant effect, rewarding properties (3, 10, and 30 mg/kg, i.p.), and the induction of immediate-early genes (IEGs), such as Arc and c-fos in the dorsal striatum (DS) and ventral striatum (VS) as well as bdnf in the medial prefrontal cortex (mPFC), of the test compounds. Our results demonstrated that all tested synthetic cathinones are potent dopamine (DA) uptake inhibitors, especially the N-ethyl analogs, while the ring-substituted cathinones tested showed higher potency as SERT inhibitors than their no ring-substituted analogs. Moreover, unlike NEP, the remaining test compounds showed clear “hybrid” properties, acting as DAT blockers but SERT substrates. Regarding the locomotion, NEP and NEPD were more efficacious (10 mg/kg) than their N-methyl analogs, which correlates with their higher potency inhibiting the DAT and an overexpression of Arc levels in the DS and VS. Furthermore, all compounds tested induced an increase in c-fos expression in the DS, except for 4-MPD, the least effective compound in inducing hyperlocomotion. Moreover, NEP induced an up-regulation of bdnf in the mPFC that correlates with its 5-HTergic properties. Finally, the present study demonstrated for the first time that NEP, 4-MPD, and 4-MeAP induce reward in mice. Altogether, this study provides valuable information about the mechanism of action and psychostimulant and rewarding properties as well as changes in the expression of IEGs related to addiction induced by novel second-generation synthetic cathinones.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Structure–Activity Relationship of Novel Second-Generation Synthetic Cathinones: Mechanism of Action, Locomotion, Reward, and Immediate-Early Genes

Nadal-Gratacós

Alberto-Silva²,

Rodríguez-Soler

et al. 2021

Front. Pharmacol.

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“…Recently, Cocchi et al (2020) reported that the phenethylamines 2C-H, 2C-I, 2C-B, and 25B-NBOMe are genotoxic in the human lymphoblastoid TK6 cells [44]. Additionally, the effects of cathinones and phenethylamines have been studied in vivo by using animal models [24,[45][46][47][48][49]. Moreover, high-resolution methods have been developed to detect these classes of NPS in different kinds of biological specimens (e.g., urine, hair, and plasma) [50,51].…”

Section: Introductionmentioning

confidence: 99%

Human Neuronal Cell Lines as An In Vitro Toxicological Tool for the Evaluation of Novel Psychoactive Substances

Sogos

Caria

Porcedda

et al. 2021

IJMS

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Novel psychoactive substances (NPS) are synthetic substances belonging to diverse groups, designed to mimic the effects of scheduled drugs, resulting in altered toxicity and potency. Up to now, information available on the pharmacology and toxicology of these new substances is very limited, posing a considerable challenge for prevention and treatment. The present in vitro study investigated the possible mechanisms of toxicity of two emerging NPS (i) 4′-methyl-alpha-pyrrolidinoexanophenone (3,4-MDPHP), a synthetic cathinone, and (ii) 2-chloro-4,5-methylenedioxymethamphetamine (2-Cl-4,5-MDMA), a phenethylamine. In addition, to apply our model to the class of synthetic opioids, we evaluated the toxicity of fentanyl, as a reference compound for this group of frequently abused substances. To this aim, the in vitro toxic effects of these three compounds were evaluated in dopaminergic-differentiated SH-SY5Y cells. Following 24 h of exposure, all compounds induced a loss of viability, and oxidative stress in a concentration-dependent manner. 2-Cl-4,5-MDMA activates apoptotic processes, while 3,4-MDPHP elicits cell death by necrosis. Fentanyl triggers cell death through both mechanisms. Increased expression levels of pro-apoptotic Bax and caspase 3 activity were observed following 2-Cl-4,5-MDMA and fentanyl, but not 3,4-MDPHP exposure, confirming the different modes of cell death.

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“…Preclinical studies investigating the effects of αPVP in rodents demonstrate avid selfadministration (26,27) and robust place preference (28), together with prolonged stimulatory effects on locomotion (29), blood pressure, and heart rate (18). While αPVP self-administration and conditioned place preference are related to drug activity at DAT, increases in blood pressure and heart rate most likely involve drug activity at NET.…”

Section: Introductionmentioning

confidence: 99%

Psychomotor stimulant effects of α-pyrrolidinovalerophenone (αPVP) enantiomers correlate with drug binding kinetics at the dopamine transporter

Niello

Sideromenos

Gradisch³

et al. 2021

Preprint

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α-Pyrrolidinovalerophenone (αPVP) is a psychostimulant and drug of abuse associated with severe intoxications in humans. αPVP exerts long-lasting psychostimulant effects, when compared to the classical dopamine transporter (DAT) inhibitor cocaine. Here, we compared the two enantiomeric forms of αPVP, the R- and the S-αPVP, with cocaine using a combination of in silico, in vitro and in vivo approaches. We found that αPVP enantiomers substantially differ from cocaine in their binding kinetics. The two enantiomers differ from each other in their association rates. However, they show similar slow dissociation rates leading to pseudo-irreversible binding kinetics at DAT. The pseudo-irreversible binding kinetics of αPVP is responsible for the observed non-competitive pharmacology and it correlates with persistent psychostimulant effects in mice. Thus, the slow binding kinetics of αPVP enantiomers profoundly differ from the fast kinetics of cocaine both in vitro and in vivo, suggesting drug-binding kinetics as a potential driver of psychostimulant effects in vivo.

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Role of amino terminal substitutions in the pharmacological, rewarding and psychostimulant profiles of novel synthetic cathinones

Cited by 25 publications

References 62 publications

Structure–Activity Relationship of Novel Second-Generation Synthetic Cathinones: Mechanism of Action, Locomotion, Reward, and Immediate-Early Genes

Structure–Activity Relationship of Novel Second-Generation Synthetic Cathinones: Mechanism of Action, Locomotion, Reward, and Immediate-Early Genes

Human Neuronal Cell Lines as An In Vitro Toxicological Tool for the Evaluation of Novel Psychoactive Substances

Psychomotor stimulant effects of α-pyrrolidinovalerophenone (αPVP) enantiomers correlate with drug binding kinetics at the dopamine transporter

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