Bifunctional compounds targeting both D2 and non-α7 nACh receptors: Design, synthesis and pharmacological characterization

• DOI: 10.1016/j.ejmech.2015.06.039
• Publication Date: 2015-06-22T21:53:00Z
• Authors: Carlo Matera; Luca Pucci; Chiara Fiorentini; Sergio Fucile; Cristina Missale; Giovanni Grazioso; Francesco Clementi; Michele Zoli; Marco De Amici; Cecilia Gotti; Clelia Dallanoce
• Keywords: 0301 basic medicine; alpha7 Nicotinic Acetylcholine Receptor; Neuronal nicotinic acetylcholine receptors alpha 4 beta 2 nAChRs; Nicotinic Antagonists; a4b2 nAChRs; Bifunctional ligands; Binding affinity; D2 receptors; Dopamine release; Electrophysiological assays; Erk phosphorylation tests; Neuronal nicotinic acetylcholine receptors; Nicotine addiction; Substrate Specificity; Bifunctional ligands; Structure-Activity Relationship; 03 medical and health sciences; Dopamine release; Humans; Nicotine addiction; Dose-Response Relationship, Drug; Molecular Structure; Receptors, Dopamine D2; D-2 receptors; a4b2 nAChRs; Bifunctional ligands; Binding affinity; D2 receptors; Dopamine release; Electrophysiological assays; Erk phosphorylation tests; Neuronal nicotinic acetylcholine receptors; Nicotine addiction; Dopamine Agonists; Dose-Response Relationship, Drug; HEK293 Cells; Humans; Molecular Structure; Nicotinic Antagonists; Receptors, Dopamine D2; Structure-Activity Relationship; Substrate Specificity; alpha7 Nicotinic Acetylcholine Receptor; Drug Design; Pharmacology; Drug Discovery3003 Pharmaceutical Science; Organic Chemistry; 3. Good health; Electrophysiological assays; Binding affinity; HEK293 Cells; Drug Design; Dopamine Agonists; Erk phosphorylation tests; bifunctional ligands; binding affinity; D(2) receptors; dopamine release; electrophysiological assays; erk phosphorylation tests; neuronal nicotinic acetylcholine receptors; nicotine addiction; α4β2 nAChRs

We designed, prepared and tested a set of structural analogs 1-4 as new hybrid compounds by incorporating, through a common alkyl chain of variable length, the pharmacophoric elements of N-n-alkyl nicotinium salts (non-α7 nicotinic acetylcholine receptors antagonists) and of 7-hydroxy-2-(aminomethyl)chromanes (dopaminergic D2 receptor agonists). The target compounds, which were assayed in binding experiments and electrophysiological, functional and Erk1/2 activation tests, essentially combined the pharmacological profiles of their individual receptor ligands. Among the studied derivatives, hybrid 2, one of the shortest homologs, in addition to the antagonist nicotinic profile similar to the other three congeners, behaved as a high affinity ligand at the investigated heteromeric nAChRs and as a low efficacy agonist at D2Rs. These bifunctional derivatives represent novel pharmacological tools in the study of nicotine addiction.