Multitarget-directed tricyclic pyridazinones as G protein-coupled receptor ligands and cholinesterase inhibitors.
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.
Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, Via Vienna 2, 07100 Sassari (Italy). pau@uniss.it.
Amedeo
A
Pau
Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via E. Orabona 4, 70125 Bari (Italy). marco.catto@uniba.it.
Marco
M
Catto
Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, Via Vienna 2, 07100 Sassari (Italy).
Giovanni
G
Pinna
Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, Via Vienna 2, 07100 Sassari (Italy).
Simona
S
Frau
Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, Via Vienna 2, 07100 Sassari (Italy).
Gabriele
G
Murineddu
Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, Via Vienna 2, 07100 Sassari (Italy).
Battistina
B
Asproni
Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, Via Vienna 2, 07100 Sassari (Italy).
Maria M
MM
Curzu
Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via E. Orabona 4, 70125 Bari (Italy).
Leonardo
L
Pisani
Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via E. Orabona 4, 70125 Bari (Italy).
Francesco
F
Leonetti
Grupo de Investigación "BioFarma" USC, Edificio CIMUS, Avda de Barcelona s/n, Planta 3, Despacho 1, 15782 Santiago de Compostela (Spain).
Maria Isabel
MI
Loza
Grupo de Investigación "BioFarma" USC, Edificio CIMUS, Avda de Barcelona s/n, Planta 3, Despacho 1, 15782 Santiago de Compostela (Spain).
José
J
Brea
Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, Via Vienna 2, 07100 Sassari (Italy).
Gérard A
GA
Pinna
Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via E. Orabona 4, 70125 Bari (Italy).
Angelo
A
Carotti
D000110:Acetylcholinesterase / Q000187:drug effects; D000818:Animals; D002091:Butyrylcholinesterase / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000378:metabolism*; D004285:Dogs; D006801:Humans; D008024:Ligands; D061985:Madin Darby Canine Kidney Cells; D011724:Pyridazines / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*
D002800:Cholinesterase Inhibitors; D008024:Ligands; D011724:Pyridazines; D043562:Receptors, G-Protein-Coupled; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
AChE inhibitors; BChE inhibitors; GPCR ligands; multitarget-directed ligands; neurodegenerative diseases