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

Pau, Amedeo and Catto, Marco and Pinna, Giovanni and Frau, Simona and Murineddu, Gabriele and Asproni, Battistina and Curzu, Maria Michela and Pisani, Leonardo and Leonetti, Francesco and Loza, Maria Isabel and Brea, José and Pinna, Gérard Aimé and Carotti, Angelo (2015) Multitarget-directed tricyclic pyridazinones as g protein-coupled receptor ligands and cholinesterase inhibitors. ChemMedChem, Vol. 10 (6), p. 1054-1070. eISSN 1860-7187. Article.

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DOI: 10.1002/cmdc.201500124


By following a multitarget ligand design approach, a library of 47 compounds was prepared, and they were tested as binders of selected G protein-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 α1A, and dopaminergic D2 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 α1A 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.

Item Type:Article
ID Code:10961
Uncontrolled Keywords:AChE inhibitors, BChE inhibitors, GPCR ligands, multitarget-directed ligands, neurodegenerative diseases
Subjects:Area 03 - Scienze chimiche > CHIM/08 Chimica farmaceutica
Divisions:001 Università di Sassari > 01-a Nuovi Dipartimenti dal 2012 > Chimica e Farmacia
Deposited On:27 May 2015 12:47

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