New Triazine Derivatives as Serotonin 5-HT6 Receptor Ligands

Abstract

Since the number of people with Alzheimer’s disease (AD) continues to rise, new and effective drugs are urgently needed to not only slow down the progression of the disease, but to stop or even prevent its development. Serotonin 5-HT6 receptor (5-HT6R) ligands are still a promising therapeutic target for the treatment of AD. 1,3,5-Triazine derivatives, as novel structures lacking an indole or a sulfone moiety, have proven to be potent ligands for this receptor. In present work, new derivatives of the compound MST4 (4-((2-isopropyl-5-methylphenoxy)methyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine), the potent 5-HT6R antagonist (Ki = 11 nM) with promising ADMET and in vivo properties, were designed. The synthesized compounds were tested for their affinity towards 5-HT6R and other receptor (off)targets (serotonin 5-HT2A, 5-HT7 and dopamine D2). Based on the new results, 4-(2-tert-butylphenoxy)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (3) was selected for extended in vitro studies as a potent and selective 5-HT6R ligand (Ki = 13 nM). Its ability to permeate the blood–brain barrier (BBB) and its hepatotoxicity were evaluated. In addition, X-ray crystallography and solubility studies were also performed. The results obtained confirm that 6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine derivatives, especially compound 3, are promising structures for further pharmacological studies as 5-HT6R ligands.

SerotoninAI: Serotonergic System Focused, Artificial Intelligence-Based Application for Drug Discovery

“…For this purpose, we reviewed the literature from 2022, when the first databases were created. New experimental data were available for seven biological targets (5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT5A, 5-HT6, and 5-HT7). − In Table , we present summary results for each receptor and the sum of predictions, using SerotoninAI, located in four categories: when the prediction difference was less than 0.5, greater than or equal to 0.5 and less than 1.0, the third group being prediction differences equal to or greater than 1.0 and less than 2.0, and the last group indicating a very large prediction difference, a value equal to or greater than 2.0. All predictions are available in Supporting Information S1.…”

“…Supporting Information S2 provides a detailed description of these results. 33 1 − − − 5-HT2A 33,34,36,37 31 15 6 − 5-HT2B 33 3 1 − − 5-HT2C 34 10 4 − − 5-HT5A 35 5 − 1 6 5-HT6 33,36,37 24 11 8 1 5-HT7 33,36,…”

Recent biological applications of heterocyclic hybrids containings-triazine scaffold

“…For this purpose, s -triazine-based compounds (74) were synthesized with N -methylpiperazine scaffold with additional ether linkages. 88 In vitro analysis of these conjugates was performed against the 5-HT 6 receptor, and it was noted that when alkyl chains are as short as only one carbon atom and the aromatic ring contains a bulky group like iso-propyl the inhibitory action is enhanced to a prominent level the inhibitor constant ( K i ) was calculated to be 11 nM ( Table 4 ).…”