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

Abstract

Owing to their multifunctional pharmacological profiles (including dual 5-HT_1A/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 μM, while compound 34 showed low hepatotoxicity even at a concentration above 50 μM.