title: Chemical, pharmacological, and in vitro metabolic stability studies on enantiomerically pure RC-33 compounds: promising neuroprotective agents acting as σ₁ receptor agonists.
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.
authors.affiliation: Department of Drug Sciences, Medicinal Chemistry and Pharmaceutical Technology Section, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Rossi
authors.forename: Alice
authors.initials: A
authors.lastname: Pedrali
authors.forename: Raffaella
authors.initials: R
authors.lastname: Gaggeri
authors.forename: Annamaria
authors.initials: A
authors.lastname: Marra
authors.forename: Luca
authors.initials: L
authors.lastname: Pignataro
authors.forename: Erik
authors.initials: E
authors.lastname: Laurini
authors.forename: Valentina
authors.initials: V
authors.lastname: Dal Col
authors.forename: Maurizio
authors.initials: M
authors.lastname: Fermeglia
authors.forename: Sabrina
authors.initials: S
authors.lastname: Pricl
authors.forename: Dirk
authors.initials: D
authors.lastname: Schepmann
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wünsch
authors.forename: Marco
authors.initials: M
authors.lastname: Peviani
authors.forename: Daniela
authors.initials: D
authors.lastname: Curti
authors.forename: Simona
authors.initials: S
authors.lastname: Collina
mesh_terms: D000818:Animals; D001665:Binding Sites; D001713:Biphenyl Compounds / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D001921:Brain / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D006168:Guinea Pigs; D008099:Liver / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D018696:Neuroprotective Agents / Q000737:chemistry / Q000378:metabolism*; D016716:PC12 Cells; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry / Q000378:metabolism; D011957:Receptors, Opioid / Q000737:chemistry / Q000378:metabolism; D017480:Receptors, sigma / Q000819:agonists* / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: C584299:1-(3-biphenyl-4-ylbutyl)piperidine; D001713:Biphenyl Compounds; D018696:Neuroprotective Agents; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D011957:Receptors, Opioid; D017480:Receptors, sigma
keywords: biological activity; enantioselectivity; in vitro metabolism; neuroprotective agents; σ1 agonists.