Pyrroloquinoline scaffold-based 5-HTR ligands: Synthesis, quantum chemical and molecular dynamic studies, and influence of nitrogen atom position in the scaffold on affinity.

Based on pyrroloquinoline scaffold bearing 5-HT agonists, a series of arylsulfonamide derivatives of 1H-pyrrolo[2,3-f]quinoline and 1H-pyrrolo[3,2-h]quinoline, substituted at position 3 with tetrahydropyridine, were synthesized and evaluated in vitro for their affinity for 5-HT receptors. A structure-activity relationship study showed that the 1H-pyrrolo[3,2-h]quinoline scaffold was more favorable for 5-HTR binding than the 1H-pyrrolo[2,3-f]quinoline one, suggesting dependence upon the type of condensation of the pyrrole and quinoline rings. As revealed by quantum-chemical calculations and molecular dynamic studies, position of the quinoline nitrogen atom in the planar pyrroloquinoline skeleton might affect the spatial orientation of the arylsulfonyl fragment, as a result of structure stabilization by internal hydrogen bonds.