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)

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• 作者：Alessandro Bonifazi ; Hideaki Yano ; Fabio Del Bello ; Aniket Farande ; Wilma Quaglia ; Riccardo Petrelli ; Rosanna Matucci ; Marta Nesi ; Giulio Vistoli ; Sergi Ferr茅 ; Alessandro Piergentili
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：November 13, 2014
• 年：2014
• 卷：57
• 期：21
• 页码：9065-9077
• 全文大小：493K
• ISSN：1520-4804

文摘

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鈥?b>f along with the intermediate alcohols 5a鈥?b>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鈥揳ctivity relationships of bivalent and linker-attached compounds in mAChRs. The hybrid 4d exhibited high efficacy for 尾-arrestin2 engagement in M₁ mAChR and alcohol 5c behaved much like 3 at M₁ mAChR and showed full antagonism in both G_i activation and 尾-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.