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

The emergence of new synthetic cathinones continues to be a matter of public health concern. In fact, they are quickly replaced by new structurally related alternatives. The main goal of the present study was to characterize the pharmacological profile, the psychostimulant and rewarding properties o...

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Autores: Duart Castells, Leticia, Nadal-Gratacós, Núria, Muralter, M., Puster, Brigitte, Berzosa, Xavier, Estrada Tejedor, Roger, Niello, Marco, Bhat, S., Pubill Sánchez, David, Camarasa García, Jordi, Sitte, Harald H., Escubedo Rafa, Elena, López Arnau, Raúl
Tipo de documento: artigo
Estado:Versão publicada
Data de publicação:2021
País:España
Recursos:Universidad de Barcelona
Repositório:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/182282
Acesso em linha:https://hdl.handle.net/2445/182282
Access Level:Acceso aberto
Palavra-chave:Dopamina
Farmacologia
Neurofarmacologia
Dopamine
Pharmacology
Neuropharmacology
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spelling Role of amino terminal substitutions in the pharmacological, rewarding and psychostimulant profiles of novel synthetic cathinonesDuart Castells, LeticiaNadal-Gratacós, NúriaMuralter, M.Puster, BrigitteBerzosa, XavierEstrada Tejedor, RogerNiello, MarcoBhat, S.Pubill Sánchez, DavidCamarasa García, JordiSitte, Harald H.Escubedo Rafa, ElenaLópez Arnau, RaúlDopaminaFarmacologiaNeurofarmacologiaDopaminePharmacologyNeuropharmacologyThe emergence of new synthetic cathinones continues to be a matter of public health concern. In fact, they are quickly replaced by new structurally related alternatives. The main goal of the present study was to characterize the pharmacological profile, the psychostimulant and rewarding properties of novel cathinones (pentedrone, N-ethyl-pentedrone, α-PVP, N,N-diethyl-pentedrone and α-PpVP) which only differs in their amino terminal substitution. Rat synaptosomes were used for [3H]dopamine uptake experiments. HEK293 transfected cells (hDAT, hSERT, hOCT; human dopamine, serotonin and organic cation transporter) were also used for [3H]monoamine uptake and transporter binding assays. Molecular docking was used to investigate the effect of the amino substitutions on the biological activity. Hyperlocomotion and conditioned place preference paradigm were used in order to study the psychostimulant and rewarding effects in mice. All compounds tested are potent inhibitors of DAT with very low affinity for SERT, hOCT-2 and -3, and their potency for inhibiting DAT increased when the amino-substituent expanded from a methyl to either an ethyl-, a pyrrolidine- or a piperidine-ring. Regarding the in vivo results, all the compounds induced an increase in locomotor activity and possess rewarding properties. Results also showed a significant correlation between predicted binding affinities by molecular docking and affinity constants (Ki) for hDAT as well as the cLogP of their amino-substituent with their hDAT/hSERT ratios. Our study demonstrates the role of the amino-substituent in the pharmacological profile of novel synthetic cathinones as well as their potency inhibiting DA uptake and ability to induce psychostimulant and rewarding effects in mice.Elsevier Ltd2021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/182282Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1016/j.neuropharm.2021.108475Neuropharmacology, 2021, vol. 186, num. 108475 (Online)https://doi.org/10.1016/j.neuropharm.2021.108475cc-by-nc-nd (c) Leticia Duart Castells, et al., 2021http://creativecommons.org/licenses/by-nc-nd/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1822822026-05-27T06:46:51Z
dc.title.none.fl_str_mv Role of amino terminal substitutions in the pharmacological, rewarding and psychostimulant profiles of novel synthetic cathinones
title Role of amino terminal substitutions in the pharmacological, rewarding and psychostimulant profiles of novel synthetic cathinones
spellingShingle Role of amino terminal substitutions in the pharmacological, rewarding and psychostimulant profiles of novel synthetic cathinones
Duart Castells, Leticia
Dopamina
Farmacologia
Neurofarmacologia
Dopamine
Pharmacology
Neuropharmacology
title_short Role of amino terminal substitutions in the pharmacological, rewarding and psychostimulant profiles of novel synthetic cathinones
title_full Role of amino terminal substitutions in the pharmacological, rewarding and psychostimulant profiles of novel synthetic cathinones
title_fullStr Role of amino terminal substitutions in the pharmacological, rewarding and psychostimulant profiles of novel synthetic cathinones
title_full_unstemmed Role of amino terminal substitutions in the pharmacological, rewarding and psychostimulant profiles of novel synthetic cathinones
title_sort Role of amino terminal substitutions in the pharmacological, rewarding and psychostimulant profiles of novel synthetic cathinones
dc.creator.none.fl_str_mv Duart Castells, Leticia
Nadal-Gratacós, Núria
Muralter, M.
Puster, Brigitte
Berzosa, Xavier
Estrada Tejedor, Roger
Niello, Marco
Bhat, S.
Pubill Sánchez, David
Camarasa García, Jordi
Sitte, Harald H.
Escubedo Rafa, Elena
López Arnau, Raúl
author Duart Castells, Leticia
author_facet Duart Castells, Leticia
Nadal-Gratacós, Núria
Muralter, M.
Puster, Brigitte
Berzosa, Xavier
Estrada Tejedor, Roger
Niello, Marco
Bhat, S.
Pubill Sánchez, David
Camarasa García, Jordi
Sitte, Harald H.
Escubedo Rafa, Elena
López Arnau, Raúl
author_role author
author2 Nadal-Gratacós, Núria
Muralter, M.
Puster, Brigitte
Berzosa, Xavier
Estrada Tejedor, Roger
Niello, Marco
Bhat, S.
Pubill Sánchez, David
Camarasa García, Jordi
Sitte, Harald H.
Escubedo Rafa, Elena
López Arnau, Raúl
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Dopamina
Farmacologia
Neurofarmacologia
Dopamine
Pharmacology
Neuropharmacology
topic Dopamina
Farmacologia
Neurofarmacologia
Dopamine
Pharmacology
Neuropharmacology
description The emergence of new synthetic cathinones continues to be a matter of public health concern. In fact, they are quickly replaced by new structurally related alternatives. The main goal of the present study was to characterize the pharmacological profile, the psychostimulant and rewarding properties of novel cathinones (pentedrone, N-ethyl-pentedrone, α-PVP, N,N-diethyl-pentedrone and α-PpVP) which only differs in their amino terminal substitution. Rat synaptosomes were used for [3H]dopamine uptake experiments. HEK293 transfected cells (hDAT, hSERT, hOCT; human dopamine, serotonin and organic cation transporter) were also used for [3H]monoamine uptake and transporter binding assays. Molecular docking was used to investigate the effect of the amino substitutions on the biological activity. Hyperlocomotion and conditioned place preference paradigm were used in order to study the psychostimulant and rewarding effects in mice. All compounds tested are potent inhibitors of DAT with very low affinity for SERT, hOCT-2 and -3, and their potency for inhibiting DAT increased when the amino-substituent expanded from a methyl to either an ethyl-, a pyrrolidine- or a piperidine-ring. Regarding the in vivo results, all the compounds induced an increase in locomotor activity and possess rewarding properties. Results also showed a significant correlation between predicted binding affinities by molecular docking and affinity constants (Ki) for hDAT as well as the cLogP of their amino-substituent with their hDAT/hSERT ratios. Our study demonstrates the role of the amino-substituent in the pharmacological profile of novel synthetic cathinones as well as their potency inhibiting DA uptake and ability to induce psychostimulant and rewarding effects in mice.
publishDate 2021
dc.date.none.fl_str_mv 2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/182282
url https://hdl.handle.net/2445/182282
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1016/j.neuropharm.2021.108475
Neuropharmacology, 2021, vol. 186, num. 108475 (Online)
https://doi.org/10.1016/j.neuropharm.2021.108475
dc.rights.none.fl_str_mv cc-by-nc-nd (c) Leticia Duart Castells, et al., 2021
http://creativecommons.org/licenses/by-nc-nd/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by-nc-nd (c) Leticia Duart Castells, et al., 2021
http://creativecommons.org/licenses/by-nc-nd/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier Ltd
publisher.none.fl_str_mv Elsevier Ltd
dc.source.none.fl_str_mv Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,301603

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