Bifunctional compounds targeting both D2 and non-α7 nACh receptors: design, synthesis and pharmacological characterization
| Autor: | Giovanni Grazioso, Marco De Amici, Francesco Clementi, Sergio Fucile, Cristina Missale, Michele Zoli, Carlo Matera, Luca Pucci, Chiara Fiorentini, Clelia Dallanoce, Cecilia Gotti |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Agonist
alpha7 Nicotinic Acetylcholine Receptor medicine.drug_class Stereochemistry Nicotinic Antagonists α4β2 nAChRs neuronal nicotinic acetylcholine receptors nicotine addiction Substrate Specificity Structure-Activity Relationship Dopamine receptor D2 binding affinity Drug Discovery medicine Structure–activity relationship Humans Nicotinic Antagonist Receptor erk phosphorylation tests Acetylcholine receptor Pharmacology Dose-Response Relationship Drug Molecular Structure Chemistry Receptors Dopamine D2 Organic Chemistry a4b2 nAChRs Bifunctional ligands Binding affinity D2 receptors Dopamine release Electrophysiological assays Erk phosphorylation tests Neuronal nicotinic acetylcholine receptors Nicotine addiction Dopamine Agonists HEK293 Cells Drug Design Drug Discovery3003 Pharmaceutical Science General Medicine Ligand (biochemistry) Nicotinic agonist D(2) receptors electrophysiological assays dopamine release bifunctional ligands |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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