Bifunctional compounds targeting both D2and non-α7 nACh receptors: Design, synthesis and pharmacological characterization

Carlo Matera, Luca Pucci, Chiara Fiorentini, Sergio Fucile, Cristina Missale, Giovanni Grazioso, Francesco Clementi, Michele Zoli, Marco De Amici, Cecilia Gotti, Clelia Dallanoce

Research output: Contribution to journalArticlepeer-review


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 D2receptor 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.

Original languageEnglish
Pages (from-to)367-383
Number of pages17
JournalEuropean Journal of Medicinal Chemistry
Publication statusPublished - Jul 10 2015


  • a4b2 nAChRs
  • Bifunctional ligands
  • Binding affinity
  • D2 receptors
  • Dopamine release
  • Electrophysiological assays
  • Erk phosphorylation tests
  • Neuronal nicotinic acetylcholine receptors
  • Nicotine addiction

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology


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