PMID- 30223122 OWN - NLM STAT- MEDLINE DCOM- 20181022 LR - 20231213 IS - 1768-3254 (Electronic) IS - 0223-5234 (Linking) VI - 158 DP - 2018 Oct 5 TI - Identification of dual Sigma1 receptor modulators/acetylcholinesterase inhibitors with antioxidant and neurotrophic properties, as neuroprotective agents. PG - 353-370 LID - S0223-5234(18)30782-7 [pii] LID - 10.1016/j.ejmech.2018.09.010 [doi] AB - In this manuscript we report on the design, synthesis and evaluation of dual Sigma 1 Receptor (S1R) modulators/Acetylcholinesterase (AChE) inhibitors endowed with antioxidant and neurotrophic properties, potentially able to counteract neurodegeneration. The compounds based on arylalkylaminoketone scaffold integrate the pharmacophoric elements of RRC-33, a S1R modulator developed by us, donepezil, a well-known AChE inhibitor, and curcumin, a natural antioxidant compound with neuroprotective properties. A small library of compounds was synthesized and preliminary in vitro screening performed. Some compounds showed good S1R binding affinity, selectivity towards S2R and N-Methyl-d-Aspartate (NMDA) receptor, AChE relevant inhibiting activity and are potentially able to bypass the BBB, as predicted by the in silico study. For the hits 10 and 20, the antioxidant profile was assessed in SH-SY5Y human neuroblastoma cell lines by evaluating their protective effect against H(2)O(2) cytotoxicity and reactive oxygen species (ROS) production. Tested compounds resulted effective in decreasing ROS production, thus ameliorating the cellular survival. Moreover, compounds 10 and 20 showed to be effective in promoting the neurite elongation of Dorsal Root Ganglia (DRG), thus demonstrating a promising neurotrophic activity. Of note, the tested compounds did not show any cytotoxic effect at the concentration assayed. Relying on these encouraging results, both compounds will undergo a structure optimization program for the development of therapeutic candidates for neurodegenerative diseases treatment. CI - Copyright (c) 2018 Elsevier Masson SAS. All rights reserved. FAU - Rui, Marta AU - Rui M AD - Department of Drug Sciences, Medicinal Chemistry, Pharmaceutical Technology and Pharmacological Sections, University of Pavia, Viale Taramelli 6 and 12, 27100 Pavia, Italy. FAU - Rossino, Giacomo AU - Rossino G AD - Department of Drug Sciences, Medicinal Chemistry, Pharmaceutical Technology and Pharmacological Sections, University of Pavia, Viale Taramelli 6 and 12, 27100 Pavia, Italy. FAU - Coniglio, Stefania AU - Coniglio S AD - Department of Drug Sciences, Medicinal Chemistry, Pharmaceutical Technology and Pharmacological Sections, University of Pavia, Viale Taramelli 6 and 12, 27100 Pavia, Italy. FAU - Monteleone, Stefania AU - Monteleone S AD - Institute of General, Inorganic and Theoretical Chemistry, University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria; Department of Pharmaceutical Chemistry, Philipps-University Marburg, Marbacher Weg 6, 35032 Marburg, Germany. FAU - Scuteri, Arianna AU - Scuteri A AD - School of Medicine and Surgery, University Milano-Bicocca, Via Cadore 48, 20900 Monza, Italy. FAU - Malacrida, Alessio AU - Malacrida A AD - School of Medicine and Surgery, University Milano-Bicocca, Via Cadore 48, 20900 Monza, Italy. FAU - Rossi, Daniela AU - Rossi D AD - Department of Drug Sciences, Medicinal Chemistry, Pharmaceutical Technology and Pharmacological Sections, University of Pavia, Viale Taramelli 6 and 12, 27100 Pavia, Italy. FAU - Catenacci, Laura AU - Catenacci L AD - Department of Drug Sciences, Medicinal Chemistry, Pharmaceutical Technology and Pharmacological Sections, University of Pavia, Viale Taramelli 6 and 12, 27100 Pavia, Italy. FAU - Sorrenti, Milena AU - Sorrenti M AD - Department of Drug Sciences, Medicinal Chemistry, Pharmaceutical Technology and Pharmacological Sections, University of Pavia, Viale Taramelli 6 and 12, 27100 Pavia, Italy. FAU - Paolillo, Mayra AU - Paolillo M AD - Department of Drug Sciences, Medicinal Chemistry, Pharmaceutical Technology and Pharmacological Sections, University of Pavia, Viale Taramelli 6 and 12, 27100 Pavia, Italy. FAU - Curti, Daniela AU - Curti D AD - Department of Biology and Biotechnology "L. Spallanzani", Lab. of Cellular and Molecular Neuropharmacology, University of Pavia, Via Ferrata 9, 27100 Pavia, Italy. FAU - Venturini, Letizia AU - Venturini L AD - Department of Internal Medicine and Therapeutics, University of Pavia, Via Taramelli 24, 27100 Pavia, Italy. FAU - Schepmann, Dirk AU - Schepmann D AD - Institute of Pharmaceutical and Medicinal Chemistry, University of Muenster, Correnstrasse 48, 48149, Muenster, Germany. FAU - Wunsch, Bernhard AU - Wunsch B AD - Institute of Pharmaceutical and Medicinal Chemistry, University of Muenster, Correnstrasse 48, 48149, Muenster, Germany. FAU - Liedl, Klaus R AU - Liedl KR AD - Institute of General, Inorganic and Theoretical Chemistry, University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria. FAU - Cavaletti, Guido AU - Cavaletti G AD - School of Medicine and Surgery, University Milano-Bicocca, Via Cadore 48, 20900 Monza, Italy. FAU - Pace, Vittorio AU - Pace V AD - Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria. FAU - Urban, Ernst AU - Urban E AD - Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria. FAU - Collina, Simona AU - Collina S AD - Department of Drug Sciences, Medicinal Chemistry, Pharmaceutical Technology and Pharmacological Sections, University of Pavia, Viale Taramelli 6 and 12, 27100 Pavia, Italy. Electronic address: simona.collina@unipv.it. LA - eng PT - Journal Article DEP - 20180908 PL - France TA - Eur J Med Chem JT - European journal of medicinal chemistry JID - 0420510 RN - 0 (Antioxidants) RN - 0 (Cholinesterase Inhibitors) RN - 0 (Neuroprotective Agents) RN - 0 (Reactive Oxygen Species) RN - 0 (Receptors, sigma) RN - 0 (Small Molecule Libraries) RN - EC 3.1.1.7 (Acetylcholinesterase) SB - IM MH - Acetylcholinesterase/*metabolism MH - Animals MH - Antioxidants/*chemistry/pharmacokinetics/*pharmacology MH - Blood-Brain Barrier/metabolism MH - Cell Survival/drug effects MH - Cholinesterase Inhibitors/*chemistry/pharmacokinetics/*pharmacology MH - Guinea Pigs MH - Humans MH - Mice MH - Molecular Docking Simulation MH - Neurodegenerative Diseases/drug therapy/metabolism MH - Neuroprotective Agents/*chemistry/pharmacokinetics/*pharmacology MH - Rats MH - Reactive Oxygen Species/metabolism MH - Receptors, sigma/*metabolism MH - Small Molecule Libraries/chemistry/pharmacokinetics/pharmacology MH - Sigma-1 Receptor OTO - NOTNLM OT - Acetylcholinesterase inhibitors OT - Antioxidant properties OT - Neuroprotective agents OT - Neurotrophic properties OT - Sigma 1 receptor EDAT- 2018/09/18 06:00 MHDA- 2018/10/23 06:00 CRDT- 2018/09/18 06:00 PHST- 2018/06/14 00:00 [received] PHST- 2018/09/03 00:00 [revised] PHST- 2018/09/04 00:00 [accepted] PHST- 2018/09/18 06:00 [pubmed] PHST- 2018/10/23 06:00 [medline] PHST- 2018/09/18 06:00 [entrez] AID - S0223-5234(18)30782-7 [pii] AID - 10.1016/j.ejmech.2018.09.010 [doi] PST - ppublish SO - Eur J Med Chem. 2018 Oct 5;158:353-370. doi: 10.1016/j.ejmech.2018.09.010. Epub 2018 Sep 8.