New Coumarin Derivatives as Cholinergic and Cannabinoid System Modulators |
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Authors: | Serena Montanari Marco Allar Laura Scalvini Magdalena Kostrzewa Federica Belluti Silvia Gobbi Marina Naldi Silvia Rivara Manuela Bartolini Alessia Ligresti Alessandra Bisi Angela Rampa |
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Institution: | 1.Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy; (S.M.); (F.B.); (S.G.); (M.N.); (M.B.);2.Endocannabinoid Research Group, Institute of Biomolecular Chemistry, National Research Council, Via Campi Flegrei 34, 80078 Pozzuoli, Italy; (M.A.); (M.K.); (A.L.);3.Department of Pharmacy, University of Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy; (L.S.); (S.R.) |
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Abstract: | In the last years, the connection between the endocannabinoid system (eCS) and neuroprotection has been discovered, and evidence indicates that eCS signaling is involved in the regulation of cognitive processes and in the pathophysiology of Alzheimer’s disease (AD). Accordingly, pharmacotherapy targeting eCS could represent a valuable contribution in fighting a multifaceted disease such as AD, opening a new perspective for the development of active agents with multitarget potential. In this paper, a series of coumarin-based carbamic and amide derivatives were designed and synthesized as multipotent compounds acting on cholinergic system and eCS-related targets. Indeed, they were tested with appropriate enzymatic assays on acetyl and butyryl-cholinesterases and on fatty acid amide hydrolase (FAAH), and also evaluated as cannabinoid receptor (CB1 and CB2) ligands. Moreover, their ability to reduce the self-aggregation of beta amyloid protein (Aβ42) was assessed. Compounds 2 and 3, bearing a carbamate function, emerged as promising inhibitors of hAChE, hBuChE, FAAH and Aβ42 self-aggregation, albeit with moderate potencies, while the amide 6 also appears a promising CB1/CB2 receptors ligand. These data prove for the new compounds an encouraging multitarget profile, deserving further evaluation. |
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Keywords: | Alzheimer’ s disease AChE BuChE FAAH CB receptors Aβ 42 self-aggregation carbamate amide |
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