Pau_2015_ChemMedChem_10_1054

Reference

Title : Multitarget-directed tricyclic pyridazinones as g protein-coupled receptor ligands and cholinesterase inhibitors - Pau_2015_ChemMedChem_10_1054
Author(s) : Pau A , Catto M , Pinna G , Frau S , Murineddu G , Asproni B , Curzu MM , Pisani L , Leonetti F , Loza MI , Brea J , Pinna GA , Carotti A
Ref : ChemMedChem , 10 :1054 , 2015
Abstract : 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 alpha1A , 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 alpha1A 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.
ESTHER : Pau_2015_ChemMedChem_10_1054
PubMedSearch : Pau_2015_ChemMedChem_10_1054
PubMedID: 25924828

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Citations formats

Pau A, Catto M, Pinna G, Frau S, Murineddu G, Asproni B, Curzu MM, Pisani L, Leonetti F, Loza MI, Brea J, Pinna GA, Carotti A (2015)
Multitarget-directed tricyclic pyridazinones as g protein-coupled receptor ligands and cholinesterase inhibitors
ChemMedChem 10 :1054

Pau A, Catto M, Pinna G, Frau S, Murineddu G, Asproni B, Curzu MM, Pisani L, Leonetti F, Loza MI, Brea J, Pinna GA, Carotti A (2015)
ChemMedChem 10 :1054