Synthesis and computer-aided analysis of the role of linker for novel ligands of the 5-HT serotonin receptor among substituted 1,3,5-triazinylpiperazines.

A series of 2-amino-4-(4-methylpiperazin-1-yl)-1,3,5-triazines was designed based on previously published 2-amino-4-benzyl-(4-methylpiperazin-1-yl)-1,3,5-triazines in order to evaluate the role of a linker between the triazine moiety and an aromatic substituent for the human serotonin 5-HT receptor affinity. As new linkers two carbon atoms (ethyl or ethenyl) or an oxyalkyl chain (methoxy, 2-ethoxy, 2-propoxy) were introduced. Affinities of the compounds for the 5-HTR as the main target, and for the 5-HTR, 5-HTR and DR as competitive ones, were determined in the radioligand binding assays. Docking to the 5-HTR homology model was performed to support SAR analysis. Results showed that the branching of the methoxyl linker increased affinity for the human 5-HTR whereas an unsaturated bond within the linker dramatically reduced desirable activity. Both experimental and theoretical studies confirmed the previously postulated beneficial role of the aromatic size for interaction with the 5-HTR. Thus, the largest naphthyl moiety yielded the highest activity. In particular, 4-(4-methylpiperazin-1-yl)-6-(1-(naphthalen-1-yloxy)ethyl)-1,3,5-triazin-2-amine (24), the most potent 5-HTR agent found (K = 23 nM), can be a new lead structure for further search and development.