TY - JOUR
T1 - Role of amino terminal substitutions in the pharmacological, rewarding and psychostimulant profiles of novel synthetic cathinones
AU - Duart-Castells, L.
AU - Nadal-Gratacós, N.
AU - Muralter, M.
AU - Puster, B.
AU - Berzosa, X.
AU - Estrada-Tejedor, R.
AU - Niello, M.
AU - Bhat, S.
AU - Pubill, D.
AU - Camarasa, J.
AU - Sitte, H. H.
AU - Escubedo, E.
AU - López-Arnau, R.
N1 - Funding Information:
This study was supported by Ministerio de Economia y Competitividad (grant number SAF2016-75347-R ), Ministerio de Ciencia e Innovación ( PID2019-109390RB-I00 ) and Plan Nacional sobre Drogas ( 2020I051 ). LDC received FPU grants from the Ministerio de Economia y Competitividad ( 15/02492 ). JC, DP and EE belong to 2017SGR979 from Generalitat de Catalunya . This work was also supported by Austrian Science Foundation (FWF) F35–B06 and W1232 (HHS) and the Vienna Science and Technology Fund (WWTF) CS15-033 (HHS). We thank Marion Holy and Kathrin Jäntsch for excellent technical assistance. NNG has also been awarded by Col·legi de Farmacèutics de Barcelona for its contribution in the synthesis section.
Publisher Copyright:
© 2021
PY - 2021/3/15
Y1 - 2021/3/15
N2 - 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.
AB - 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.
KW - Dopamine
KW - Dopamine transporter
KW - New psychoactive substances
KW - Psychostimulant
KW - Reward
KW - Synthetic cathinones
UR - http://www.scopus.com/inward/record.url?scp=85100406020&partnerID=8YFLogxK
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=pure_univeritat_ramon_llull&SrcAuth=WosAPI&KeyUT=WOS:000628451100001&DestLinkType=FullRecord&DestApp=WOS_CPL
UR - http://hdl.handle.net/20.500.14342/3620 DOI
U2 - 10.1016/j.neuropharm.2021.108475
DO - 10.1016/j.neuropharm.2021.108475
M3 - Article
C2 - 33529677
AN - SCOPUS:85100406020
SN - 0028-3908
VL - 186
JO - Neuropharmacology
JF - Neuropharmacology
M1 - 108475
ER -