Aminotriazines with indole motif as novel, 5-HT7 receptor ligands with atypical binding mode

Design, Synthesis and Biological Evaluation of Novel 1,3,5-Triazines: Effect of Aromatic Ring Decoration on Affinity to 5-HT7 Receptor

“…Both ligands have more linear bioconformation ( Figure 5 ) with a clear bend of the alkylaromatic moiety and almost completely overlapping hydrogen bonds with the following amino acids: Glu366 (E7.34), Asp162 (D3.32), Ile233, Ser243 (S5.42) (for ligand 2 ), and π–π stacking hydrophobic interactions with the following amino acids: Trp340 (W6.48) and Phe343 (F6.51). The binding mode for ligands 2 and 12 corresponds to the results reported previously [ 15 , 17 , 20 , 26 ].…”

“…First, amines 61 – 68 were obtained in the reaction of 2-chloroethylamine hydrochloride 52 and appropriately substituted aniline 53 – 60 . Subsequently, the resulting compounds reacted with readily available [ 20 ] core compound 69 in the presence of K 2 CO 3 and microwave irradiation ( p = 50 W) for 2.5 min [ 15 ]. Final type 2 compounds were isolated with yields of 43–75%.…”

“…Only the ligand with an unsubstituted benzimidazole ring ( 17 ) had a moderate activity with K i = 227 nM. The type 4 compounds are also found to be inactive ( 20 , 21 ) or weakly active ( 22 ), but they provide further evidence of the significant effect of the linker between the triazine core and the aromatic system [ 20 ]. When analyzing affinity to the other receptors tested (5-HT 1A , 5-HT 2A , 5-HT 6, and D 2 ), most of the designed compounds have no activity ( K i > 1000 nM) or low activity (500 nM < K i < 1000 nM).…”

“…The highly active compounds ( 2 K i = 8 nM and 12 K i = 18 nM) were selected for studying their bioconformation and binding modes through molecular modeling using Induced Fit Docking (Schrodinger, Maestro [ 25 ]) followed by ligand–receptor complex optimization using a QM-MM mixed quantum mechanical method (Schrodinger, Maestro [ 25 ]) [ 15 , 20 ]. Both ligands occupy a binding pocket typical of 5-HT 7 receptor ligands [ 26 ].…”

“…Another argument for synthesizing indole derivatives is the effect of heteroatoms on ADME-T parameters, particularly the fluorine atom [ 18 , 19 ]. We showed [ 20 ] that the compounds tested without any ring substituent ( Figure 1 A) had low in vitro metabolic stability. By incorporating chlorine in the structure [ 15 ] ( Figure 1 B), metabolic stability increased with a slight decrease in cytotoxicity in the HepG2 cell line.…”