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.

Bifunctional compounds targeting both D2 and non-α7 nACh receptors: design, synthesis and pharmacological characterization / Matera, Carlo; Pucci, Luca; Fiorentini, Chiara; Fucile, Sergio; Missale, Cristina; Grazioso, Giovanni; Clementi, Francesco; Zoli, Michele; De Amici, Marco; Gotti, Cecilia; Dallanoce, Clelia. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - STAMPA. - 101:(2015), pp. 367-383. [10.1016/j.ejmech.2015.06.039]

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

FUCILE, Sergio;
2015

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.
2015
bifunctional ligands; binding affinity; D(2) receptors; dopamine release; electrophysiological assays; erk phosphorylation tests; neuronal nicotinic acetylcholine receptors; nicotine addiction; α4β2 nAChRs
01 Pubblicazione su rivista::01a Articolo in rivista
Bifunctional compounds targeting both D2 and non-α7 nACh receptors: design, synthesis and pharmacological characterization / Matera, Carlo; Pucci, Luca; Fiorentini, Chiara; Fucile, Sergio; Missale, Cristina; Grazioso, Giovanni; Clementi, Francesco; Zoli, Michele; De Amici, Marco; Gotti, Cecilia; Dallanoce, Clelia. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - STAMPA. - 101:(2015), pp. 367-383. [10.1016/j.ejmech.2015.06.039]
File allegati a questo prodotto
File Dimensione Formato  
Matera_Bifunctional_2015.pdf

solo gestori archivio

Tipologia: Versione editoriale (versione pubblicata con il layout dell'editore)
Licenza: Tutti i diritti riservati (All rights reserved)
Dimensione 1.74 MB
Formato Adobe PDF
1.74 MB Adobe PDF   Contatta l'autore

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/788239
Citazioni
  • ???jsp.display-item.citation.pmc??? 1
  • Scopus 12
  • ???jsp.display-item.citation.isi??? 12
social impact