Impact of the Substitution Pattern at the Basic Center and Geometry of the Amine Fragment on 5-HT 6 and D 3 R Affinity in the 1 H -Pyrrolo[3,2- c ]quinoline Series.

Salt bridge (SB, double-charge-assisted hydrogen bonds) formation is one of the strongest molecular non-covalent interactions in biological systems, including ligand–receptor complexes. In the case of G-protein-coupled receptors, such an interaction is formed by the conserved aspartic acid (D3.32) residue and the basic moiety of the aminergic ligand. This study aims to determine the influence of the substitution pattern at the basic nitrogen atom and the geometry of the amine moiety at position 4 of 1H-pyrrolo[3,2-c]quinoline on the quality of the salt bridge formed in the 5-HT₆ receptor and D₃ receptor. To reach this goal, we synthetized and biologically evaluated a new series of 1H-pyrrolo[3,2-c]quinoline derivatives modified with various amines. The selected compounds displayed a significantly higher 5-HT₆R affinity and more potent 5-HT₆R antagonist properties when compared with the previously identified compound PZ-1643, a dual-acting 5-HT₆R/D₃R antagonist; nevertheless, the proposed modifications did not improve the activity at D₃R. As demonstrated by the in silico experiments, including molecular dynamics simulations, the applied structural modifications were highly beneficial for the formation and quality of the SB formation at the 5-HT₆R binding site; however, they are unfavorable for such interactions at D₃R. [ABSTRACT FROM AUTHOR]