Impact of the Substitution Pattern at the Basic Center and Geometry of the Amine Fragment on 5-HT and DR Affinity in the 1-Pyrrolo[3,2-]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 1-pyrrolo[3,2-]quinoline on the quality of the salt bridge formed in the 5-HT receptor and D receptor. To reach this goal, we synthetized and biologically evaluated a new series of 1-pyrrolo[3,2-]quinoline derivatives modified with various amines. The selected compounds displayed a significantly higher 5-HTR affinity and more potent 5-HTR antagonist properties when compared with the previously identified compound , a dual-acting 5-HTR/DR antagonist; nevertheless, the proposed modifications did not improve the activity at DR. 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-HTR binding site; however, they are unfavorable for such interactions at DR.