Methylpiperidinium Iodides as novel antagonists for alpha 7 nicotinic acetylcholine receptors

Abstract

The alpha 7 nicotinic acetylcholine receptor (nAChR) is expressed in neuronal and non-neuronal cells and is involved in several physiopathological processes, and is thus an important drug target. We have designed and synthesized novel piperidine derivatives as alpha 7 nAChR antagonists. Thus, we describe here a new series of 1-[2-(4-alkoxy-phenoxy-ethyl)]piperidines and 1-[2-(4-alkyloxy-phenoxy-ethyl)]-1-methylpiperidinium iodides (compounds 11a-11c and 12a-12c), and their actions on alpha 7 nAChRs. The pharmacological activity of these compounds was studied in rat CA1 hippocampal interneurons by using the whole-cell voltage-clamp technique. Inhibition of the choline-induced current was less for 11a-11c than for the methylpiperidinium iodides 12a-12c and depended on the length of the aliphatic chain. Those compounds showing strong effects were studied further using molecular docking and molecular dynamics simulations. The strongest and non-voltage dependent antagonism was shown by 12a, which could establish cation-pi interactions with the principal (C)side and van der Waals interactions with the complementary (-)-side in the alpha 7 nAChRs. Furthermore, compound 11a forms hydrogen bonds with residue Q115 of the complementary (-)-side through water molecules without forming cation-pi interactions. Our findings have led to the establishment of a new family of antagonists that interact with the agonist binding cavity of the alpha 7 nAChR, which represent a promising new class of compounds for the treatment of pathologies where these receptors need to be negatively modulated, including neuropsychiatric disorders as well as different types of cancer.