TY - JOUR
T1 - Bifunctional compounds targeting both D2and non-α7 nACh receptors
T2 - Design, synthesis and pharmacological characterization
AU - Matera, Carlo
AU - Pucci, Luca
AU - Fiorentini, Chiara
AU - Fucile, Sergio
AU - Missale, Cristina
AU - Grazioso, Giovanni
AU - Clementi, Francesco
AU - Zoli, Michele
AU - De Amici, Marco
AU - Gotti, Cecilia
AU - Dallanoce, Clelia
PY - 2015/7/10
Y1 - 2015/7/10
N2 - 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.
AB - 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.
KW - a4b2 nAChRs
KW - Bifunctional ligands
KW - Binding affinity
KW - D2 receptors
KW - Dopamine release
KW - Electrophysiological assays
KW - Erk phosphorylation tests
KW - Neuronal nicotinic acetylcholine receptors
KW - Nicotine addiction
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U2 - 10.1016/j.ejmech.2015.06.039
DO - 10.1016/j.ejmech.2015.06.039
M3 - Article
C2 - 26164842
AN - SCOPUS:84949534095
VL - 101
SP - 367
EP - 383
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
ER -