Design and synthesis of new potent 5-HT7 receptor ligands as a candidate for the treatment of central nervous system diseases

Owing to their multifunctional pharmacological profiles (including dual 5-HT1A/5-HT7 action), arylpiperazine derivatives are widely used for treating central nervous system diseases including the depression or neuropathic pain. Herein we describe the design, synthesis and evaluation of biological activity of novel 5-HT7 ligands derived of 2,4,6-triamino-1,3,5-triazine. The studied compounds showed affinity and high selectively towards 5-HT7 receptor with the two most active compounds 34 (K-i = 61 nM), 22 (K-i = 109 nM) showing good metabolic stability and moderate affinity to CYP3A4 isoenzyme. Compound 22 had high hepatotoxicity at a concentration below 50 mu M, while compound 34 showed low hepatotoxicity even at a concentration above 50 mu M. (C) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

Arylpiperazine derivatives with dual 5-HT1A/5-HT7 action are widely used for treating central nervous system diseases; two newly designed 5-HT7 ligands showed good metabolic stability and different hepatotoxicity performances.