Chemical,Pharmacological, and in vitro Metabolic Stability Studies on Enantiomerically Pure RC‐33 Compounds: Promising Neuroprotective Agents Acting as σ1 Receptor Agonists |
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| Authors: | Dr. Daniela Rossi Dr. Alice Pedrali Dr. Raffaella Gaggeri Dr. Annamaria Marra Dr. Luca Pignataro Dr. Erik Laurini Dr. Valentina Dal Col Prof. Maurizio Fermeglia Prof. Sabrina Pricl Dr. Dirk Schepmann Prof. Bernhard Wünsch Dr. Marco Peviani Dr. Daniela Curti Prof. Simona Collina |
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| Affiliation: | 1. Department of Drug Sciences, Medicinal Chemistry and Pharmaceutical Technology Section, University of Pavia, Viale Taramelli 12, 27100 Pavia (Italy);2. Dipartimento di Chimica, Università degli Studi di Milano, Istituto di Scienze e Tecnologie Molecolari (ISTM) del CNR, Via Golgi 19, 20133 Milan (Italy);3. MOSE‐DEA, University of Trieste, Via Valerio 10, 34127 Trieste (Italy);4. National Interuniversity Consortium for Material Science and Technology (INSTM), Research Unit MOSE‐DEA, University of Trieste, Trieste (Italy);5. Institute of Pharmaceutical and Medicinal Chemistry, University of Muenster, Correnstrasse 48, 48149 Münster (Germany);6. Department of Biology and Biotechnology “L. Spallanzani”, Laboratory of Cellular and Molecular Neuropharmacology, University of Pavia, Via Ferrata 9, 27100 Pavia (Italy) |
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| Abstract: | Our recent research efforts identified racemic RC‐33 as a potent and metabolically stable σ1 receptor agonist. Herein we describe the isolation of pure RC‐33 enantiomers by chiral chromatography, assignment of their absolute configuration, and in vitro biological studies in order to address the role of chirality in the biological activity of these compounds and their metabolic processing. The binding of enantiopure RC‐33 to the σ1 receptor was also investigated in silico by molecular dynamics simulations. Both RC‐33 enantiomers showed similar affinities for the σ1 receptor and appeared to be almost equally effective as σ1 receptor agonists. However, the R‐configured enantiomer showed higher in vitro hepatic metabolic stability in the presence of NADPH than the S enantiomer. Overall, the results presented herein led us to select (R)‐RC‐33 as the optimal candidate for further in vivo studies in an animal model of amyotrophic lateral sclerosis. |
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| Keywords: | biological activity enantioselectivity in vitro metabolism neuroprotective agents σ 1 agonists. |
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