Bifunctional compounds targeting both D2 and non-α7 nACh receptors: design, synthesis and pharmacological characterization
- PMID:26164842
- DOI: 10.1016/j.ejmech.2015.06.039
Bifunctional compounds targeting both D2 and non-α7 nACh receptors: design, synthesis and pharmacological characterization
Abstract
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.
Keywords: Bifunctional ligands; Binding affinity; D(2) receptors; Dopamine release; Electrophysiological assays; Erk phosphorylation tests; Neuronal nicotinic acetylcholine receptors; Nicotine addiction; α4β2 nAChRs.
Copyright © 2015 Elsevier Masson SAS. All rights reserved.
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