Novel bitopic hybrids, based on the M<inf>1</inf>/M<inf>4</inf> muscarinic acetylcholine receptor (mAChR) orthosteric agonist xanomeline (1) and the putative M<inf>1</inf> mAChR allosteric agonist 1-[3-(4-butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1, 3) connected by an aliphatic linker of variable length, were prepared. The novel heterobivalent hybrids 4a-f along with the intermediate alcohols 5a-f were pharmacologically evaluated in radioligand binding assays and some of them for their functional efficacies in bioluminescence resonance energy transfer (BRET)-based assays to give an insight into the structure-activity relationships of bivalent and linker-attached compounds in mAChRs. The hybrid 4d exhibited high efficacy for β-arrestin2 engagement in M<inf>1</inf> mAChR and alcohol 5c behaved much like 3 at M<inf>1</inf> mAChR and showed full antagonism in both G<inf>i</inf> activation and β-arrestin2 engagement at M<inf>4</inf> mAChR. Moreover, docking simulations on the M<inf>1</inf> mAChR model were performed to elucidate how the binding mode of the proposed compounds is influenced by the linker length.

Synthesis and biological evaluation of a novel series of heterobivalent muscarinic ligands based on xanomeline and 1-[3-(4-butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1) / A. Bonifazi, H. Yano, F. Del Bello, A. Farande, W. Quaglia, R. Petrelli, R. Matucci, M. Nesi, G. Vistoli, S. Ferré, A. Piergentili. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 57:21(2014 Nov 13), pp. 9065-9077. [10.1021/jm501173q]

Synthesis and biological evaluation of a novel series of heterobivalent muscarinic ligands based on xanomeline and 1-[3-(4-butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1)

G. Vistoli;
2014

Abstract

Novel bitopic hybrids, based on the M1/M4 muscarinic acetylcholine receptor (mAChR) orthosteric agonist xanomeline (1) and the putative M1 mAChR allosteric agonist 1-[3-(4-butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1, 3) connected by an aliphatic linker of variable length, were prepared. The novel heterobivalent hybrids 4a-f along with the intermediate alcohols 5a-f were pharmacologically evaluated in radioligand binding assays and some of them for their functional efficacies in bioluminescence resonance energy transfer (BRET)-based assays to give an insight into the structure-activity relationships of bivalent and linker-attached compounds in mAChRs. The hybrid 4d exhibited high efficacy for β-arrestin2 engagement in M1 mAChR and alcohol 5c behaved much like 3 at M1 mAChR and showed full antagonism in both Gi activation and β-arrestin2 engagement at M4 mAChR. Moreover, docking simulations on the M1 mAChR model were performed to elucidate how the binding mode of the proposed compounds is influenced by the linker length.
Animals; CHO Cells; Cricetulus; Molecular Docking Simulation; Muscarinic Agonists; Piperidines; Pyridines; Quinolones; Receptor, Muscarinic M1; Structure-Activity Relationship; Thiadiazoles; Molecular Medicine; Drug Discovery3003 Pharmaceutical Science; Medicine (all)
Settore CHIM/08 - Chimica Farmaceutica
http://pubs.acs.org/jmc
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/340364
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