New piperidine derivatives. Studies in silico on α7 nicotinic acetylcholine receptors

A series of new derivatives of piperidine (1a and 2a) were designed, synthesized and chemically characterized. Additionally, electrophysiological recordings of the I_Ch (Ch-induced current) in interneurons from the hippocampal indicated that the compound 2a inhibited the I_Ch more strongly than the corresponding compound 1a, 2a showing the most potent antagonistic effect on α7-containing nAChRs. The molecular docking studies and molecular dynamics simulations give us new insights about these findings. In this regard, the compound 2a forms cation-π interactions with the aromatic cage (residues Y89, W143 Y185, Y192 of the principal (+)-side and W53 of the complementary (-)-side) of the α7 nAChR, important for ligand affinity to the α7 nAChR¹. In further, the aliphatic chain of 2a presents van der Waals interactions with L106 and Q115 of the complementary (-)-side. These interactions were conserved during almost all molecular dynamics simulation time (20 ns) preventing both conformational changes of the receptor and its activation, which may account for the slow recovery of the I_Ch inhibition observed in electrophysiological assays. Regarding with the non-methylated compound 1a the piperidine nitrogen of the compound is protonated at physiological pH, producing a hydrogen bond that forms a solvation network with the water molecules in the binding cavity of the α7 nAChR (see Figure 1). As in the case of 2a during the molecular dynamics simulation, the aliphatic chain of 1a maintains van der Waals interactions with Q115, helping to stabilize the ligand in the cavity. These interactions may allow activation of the receptor diminishing the antagonism activity.