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

NEUROPHARMACOLOGY

卷:186

Article

Duart-Castells, L.^1,2  Nadal-Gratacos, N.³  Muralter, M.^1,2  Puster, B.^1,2  Berzosa, X.³  Estrada-Tejedor, R.³  Niello, M.⁴  Bhat, S.⁴  Pubill, D.^1,2  Camarasa, J.^1,2  Sitte, H. H.^4,5  Escubedo, E.^1,2  Lopez-Arnau, R.^1,2 

[1] Univ Barcelona, Dept Pharmacol Toxicol & Therapeut Chem, Pharmacol Sect, Barcelona, Spain

[2] Univ Barcelona, Inst Biomed IBUB, Fac Pharm, Barcelona, Spain

[3] Univ Ramon Llull, IQS Sch Engn, Pharmaceut Chem Grp GQF, Barcelona, Spain

[4] Med Univ Vienna, Ctr Physiol & Pharmacol, Inst Pharmacol, A-1090 Vienna, Austria

[5] Med Univ Vienna, Ctr Addict Res & Sci, Waehringerstr 13 A, A-1090 Vienna, Austria

关键词: New psychoactive substances;    Synthetic cathinones;    Psychostimulant;    Reward;    Dopamine;    Dopamine transporter;   

DOI  :  10.1016/j.neuropharm.2021.108475

来源: Elsevier

【 摘 要 】

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, Nethyl-pentedrone, alpha-PVP, N,N-diethyl-pentedrone and alpha-PpVP) which only differs in their amino terminal substitution. Rat synaptosomes were used for [H-3]dopamine uptake experiments. HEK293 transfected cells (hDAT, hSERT, hOCT; human dopamine, serotonin and organic cation transporter) were also used for [H-3]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 loco motor 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 aminosubstituent 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.

【 授权许可】

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