Minimal Structural Changes Determine Full and Partial Nicotinic Receptor Agonist Activity for Nicotine Analogues

Gonzalez-Gutierrez J.P.; Hodar M.; Viscarra F.; Paillali P.; Guerra-Díaz N.; Pessoa-Mahana H.; Hernández-Morantes J.J.; Pérez-Sánchez H.; Bermúdez I.; Reyes-Parada M.; Iturriaga-Vásquez P.

Abstract

Neuronal alpha 4 beta 2 nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels (LGIC) that have been implicated in nicotine addiction, reward, cognition, pain disorders, anxiety, and depression. Nicotine has been widely used as a template for the synthesis of ligands that prefer alpha 4 beta 2 nAChRs subtypes. The most important therapeutic use for alpha 4 beta 2 nAChRs is as replacement therapy for smoking cessation and withdrawal and the most successful therapeutic ligands are partial agonists. In this case, we use the N-methylpyrrolidine moiety of nicotine to design and synthesize new alpha 4 beta 2 nicotinic derivatives, coupling the pyrrolidine moiety to an aromatic group by introducing an ether-bonded functionality. Meta-substituted phenolic derivatives were used for these goals. Radioligand binding assays were performed on clonal cell lines of h alpha 4 beta 2 nAChR and two electrode voltage-clamp experiments were used for functional assays. Molecular docking was performed in the open state of the nAChR in order to rationalize the agonist activity shown by our compounds.

Más información

Título según WOS: Minimal Structural Changes Determine Full and Partial Nicotinic Receptor Agonist Activity for Nicotine Analogues
Título según SCOPUS: Minimal structural changes determine full and partial nicotinic receptor agonist activity for nicotine analogues
Título de la Revista: MOLECULES
Volumen: 24
Número: 15
Editorial: MDPI
Fecha de publicación: 2019
Idioma: English
DOI:

10.3390/molecules24152684

Notas: ISI, SCOPUS