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Link to original content: https://pubmed.ncbi.nlm.nih.gov/26164842
Bifunctional compounds targeting both D2 and non-α7 nACh receptors: design, synthesis and pharmacological characterization - PubMed Skip to main page content
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. 2015 Aug 28:101:367-83.
doi: 10.1016/j.ejmech.2015.06.039. Epub 2015 Jun 20.

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

Carlo Matera  1 , Luca Pucci  2 , Chiara Fiorentini  3 , Sergio Fucile  4 , Cristina Missale  3 , Giovanni Grazioso  1 , Francesco Clementi  2 , Michele Zoli  5 , Marco De Amici  1 , Cecilia Gotti  6 , Clelia Dallanoce  7
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Bifunctional compounds targeting both D2 and non-α7 nACh receptors: design, synthesis and pharmacological characterization

Carlo Matera et al. Eur J Med Chem. .

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.

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