title: 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).
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.
authors.affiliation: Scuola di Scienze del Farmaco e dei Prodotti della Salute, Università di Camerino , Via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bonifazi
authors.forename: Hideaki
authors.initials: H
authors.lastname: Yano
authors.forename: Fabio
authors.initials: F
authors.lastname: Del Bello
authors.forename: Aniket
authors.initials: A
authors.lastname: Farande
authors.forename: Wilma
authors.initials: W
authors.lastname: Quaglia
authors.forename: Riccardo
authors.initials: R
authors.lastname: Petrelli
authors.forename: Rosanna
authors.initials: R
authors.lastname: Matucci
authors.forename: Marta
authors.initials: M
authors.lastname: Nesi
authors.forename: Giulio
authors.initials: G
authors.lastname: Vistoli
authors.forename: Sergi
authors.initials: S
authors.lastname: Ferré
authors.forename: Alessandro
authors.initials: A
authors.lastname: Piergentili
mesh_terms: D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D062105:Molecular Docking Simulation; D018721:Muscarinic Agonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry; D015363:Quinolones / Q000737:chemistry* / Q000494:pharmacology; D043643:Receptor, Muscarinic M1 / Q000187:drug effects; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000737:chemistry
chemical_list: C531940:77-LH-28-1; D018721:Muscarinic Agonists; D010880:Piperidines; D011725:Pyridines; D015363:Quinolones; D043643:Receptor, Muscarinic M1; D013830:Thiadiazoles; C075257:xanomeline