Design and synthesis of new potent 5-HT 7 receptor ligands as a candidate for the treatment of central nervous system diseases

• Published in: European journal of medicinal chemistry 2022-01, Vol.227, p.113931
• Main Authors: Kułaga, Damian, Drabczyk, Anna K, Satała, Grzegorz, Latacz, Gniewomir, Rózga, Karolina, Plażuk, Damian, Jaśkowska, Jolanta
• Format: Article
• Language: English
• Subjects: Cell Proliferation - drug effects; Cell Survival - drug effects; Central Nervous System Diseases - drug therapy; Central Nervous System Diseases - metabolism; Dose-Response Relationship, Drug; Drug Design; Hep G2 Cells; Humans; Ligands; Models, Molecular; Molecular Structure; Receptors, Serotonin - metabolism; Structure-Activity Relationship; Triazines - chemical synthesis; Triazines - chemistry; Triazines - pharmacology
• ISSN: 1768-3254
• DOI: 10.1016/j.ejmech.2021.113931

Owing to their multifunctional pharmacological profiles (including dual 5-HT /5-HT 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-HT ligands derived of 2,4,6-triamino-1,3,5-triazine. The studied compounds showed affinity and high selectively towards 5-HT receptor with the two most active compounds 34 (K  = 61 nM), 22 (K  = 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.