By following a multitarget ligand design approach, a library of 47 compounds was prepared, and they were tested as binders of selected Gprotein-coupled receptors (GPCRs) and inhibitors of acetyl and/or butyryl cholinesterase. The newly designed ligands feature pyridazinone-based tricyclic scaffolds connected through alkyl chains of variable length to proper amine moieties (e.g., substituted piperazines or piperidines) for GPCR and cholinesterase (ChE) molecular recognition. The compounds were tested at three different GPCRs, namely serotoninergic 5-HT1A, adrenergic (1A), and dopaminergic D-2 receptors. Our main goal was the discovery of compounds that exhibit, in addition to ChE inhibition, antagonist activity at 5-HT1A because of its involvement in neuronal deficits typical of Alzheimer's and other neurodegenerative diseases. Ligands with nanomolar affinity for the tested GPCRs were discovered, but most of them behaved as dual antagonists of (1A) and 5-HT1A receptors. Nevertheless, several compounds displaying this GPCR affinity profile also showed moderate to good inhibition of AChE and BChE, thus deserving further investigations to exploit the therapeutic potential of such unusual biological profiles.

Multitarget-directed tricyclic pyridazinones as G protein-coupled receptor ligands and cholinesterase inhibitors / Pau, Amedeo; Catto, Marco; Pinna, Giovanni; Frau, Simona; Murineddu, Gabriele; Asproni, Battistina; Curzu, Maria M.; Pisani, Leonardo; Leonetti, Francesco; Loza, Maria Isabel; Brea, Jose; Pinna, Gerard Aime; Carotti, Angelo. - In: CHEMMEDCHEM. - ISSN 1860-7187. - 10:6(2015), pp. 1054-1070. [10.1002/cmdc.201500124]

Multitarget-directed tricyclic pyridazinones as G protein-coupled receptor ligands and cholinesterase inhibitors

PAU, Amedeo
;
MURINEDDU, Gabriele
Methodology
;
ASPRONI, Battistina
Resources
;
PINNA, Gerard Aime;
2015-01-01

Abstract

By following a multitarget ligand design approach, a library of 47 compounds was prepared, and they were tested as binders of selected Gprotein-coupled receptors (GPCRs) and inhibitors of acetyl and/or butyryl cholinesterase. The newly designed ligands feature pyridazinone-based tricyclic scaffolds connected through alkyl chains of variable length to proper amine moieties (e.g., substituted piperazines or piperidines) for GPCR and cholinesterase (ChE) molecular recognition. The compounds were tested at three different GPCRs, namely serotoninergic 5-HT1A, adrenergic (1A), and dopaminergic D-2 receptors. Our main goal was the discovery of compounds that exhibit, in addition to ChE inhibition, antagonist activity at 5-HT1A because of its involvement in neuronal deficits typical of Alzheimer's and other neurodegenerative diseases. Ligands with nanomolar affinity for the tested GPCRs were discovered, but most of them behaved as dual antagonists of (1A) and 5-HT1A receptors. Nevertheless, several compounds displaying this GPCR affinity profile also showed moderate to good inhibition of AChE and BChE, thus deserving further investigations to exploit the therapeutic potential of such unusual biological profiles.
2015
Multitarget-directed tricyclic pyridazinones as G protein-coupled receptor ligands and cholinesterase inhibitors / Pau, Amedeo; Catto, Marco; Pinna, Giovanni; Frau, Simona; Murineddu, Gabriele; Asproni, Battistina; Curzu, Maria M.; Pisani, Leonardo; Leonetti, Francesco; Loza, Maria Isabel; Brea, Jose; Pinna, Gerard Aime; Carotti, Angelo. - In: CHEMMEDCHEM. - ISSN 1860-7187. - 10:6(2015), pp. 1054-1070. [10.1002/cmdc.201500124]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11388/46150
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