Identification of RC-33 as a potent and selective σ1 receptor agonist potentiating NGF-induced neurite outgrowth in PC12 cells. Part 2: g-Scale synthesis, physicochemical characterization and in vitro metabolic stability

Rossi, Daniela; Marra, Annamaria; Picconi, Pietro; Serra, Massimo; Catenacci, Laura; Sorrenti, Milena; Laurini, Erik; Fermeglia, Maurizio; Pricl, Sabrina; Brambilla, Stefania; Almirante, Nicoletta; Peviani, Marco; Curti, Daniela; Collina, Simona

doi:10.1016/j.bmc.2013.02.029

Cited by 37 publications

(26 citation statements)

References 74 publications

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“…), showing excellent σ 1 receptor affinity ( K i = 0.70 ± 0.3 nM), combined with high selectivity over various receptors expressed in the CNS . Additionally, rac ‐ RC-33 · HCl turned out to be a potent σ 1 receptor agonist in our validated PC12 cell model of neuronal differentiation and showed high metabolic stability in several biological matrices (i.e., mouse and rat blood, rat, dog, and human plasma) . Accordingly rac ‐ RC-33 · HCl was identified as the optimal candidate to be further investigated.…”

Section: Introductionmentioning

confidence: 88%

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Studies on the Enantiomers of RC-33 as Neuroprotective Agents: Isolation, Configurational Assignment, and Preliminary Biological Profile

et al. 2013

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In this study we addressed the role of chirality in the biological activity of RC-33, recently studied by us in its racemic form. An asymmetric synthesis procedure was the first experiment, leading to the desired enantioenriched RC-33 but with an enantiomeric excess (ee) not good enough for supporting the in vitro investigation. An enantioselective high-performance liquid chromatography (HPLC) procedure was then successfully carried out, yielding both RC-33 enantiomers in amounts and optical purity suitable for the pharmacological study. The absolute configuration of pure enantiomers was easily assigned exploiting the asymmetric synthesis previously devised. As emerged in the preliminary in vitro biological investigation, (S)- and (R)-RC-33 possess a comparable affinity towards the σ1 receptor and a very a similar behavior in the calcium influx assay, resulting in an equally effective σ1 receptor agonist. Overall, the results obtained so far suggest that the interaction with the biological target is nonstereoselective and leads us to hypothesize that there is a lack of stereoselectivity in the biological activity of RC-33.

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Section: Introductionmentioning

confidence: 88%

“…In the last 10 years our research group has conducted extensive studies aimed at discovering novel σ 1 receptor ligands as potential neuroprotective agents . In this context, a drug discovery library based on arylalkenyl‐ and arylalkylaminic scaffolds was prepared (Fig.…”

Section: Introductionmentioning

confidence: 99%

Studies on the Enantiomers of RC-33 as Neuroprotective Agents: Isolation, Configurational Assignment, and Preliminary Biological Profile

et al. 2013

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“…All MD simulations were carried out using the Pmemd modules of Amber 14 [66] running on aC PU/GPU calculation cluster.T he binding free energy, DG calcd ,b etween the selected compounds and the s 1 receptor was estimated by resorting to the MM/PBSA [67] approach implemented in Amber 14, according to aw ell-validated methodology. [45,[68][69][70][71][72][73][74] Molecular graphics images were produced using the UCSF Chimera package (v.1.10). [75] The interaction spectra were obtained using GraphPad Prism version 6.00 for Mac OS XY osemite (GraphPad Software, La Jolla, CA, USA).…”

Section: Affinity Toward S 1 and S 2 Receptorsmentioning

confidence: 99%

Thiazole‐Based σ₁ Receptor Ligands: Diversity by Late‐Stage C−H Arylation of Thiazoles, Structure–Affinity and Selectivity Relationships, and Molecular Interactions

et al. 2017

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Spirocyclic thiophene derivatives represent promising σ ligands with high σ affinity and selectivity over the σ subtype. To increase ligand efficiency, the thiophene ring was replaced bioisosterically by a thiazole ring, and the pyran ring was opened. Late-stage diversification by regioselective C-H arylation of thiazoles 9 a-c resulted in a set of 53 compounds with high diversity. This set of compounds was analyzed with respect to σ affinity, σ /σ selectivity, lipophilicity (logD ), lipophilicity-corrected ligand efficiency (LELP), and molecular target interactions. The most promising candidates were pyridyl-substituted thiazole derivatives 33 c (2-(1-benzyl-4-ethoxypiperidin-4-yl)-5-(pyridin-3-yl)thiazole) and 34 c (2-(1-benzyl-4-ethoxypiperidin-4-yl)-5-(pyridin-4-yl)thiazole), possessing low-nanomolar σ affinity (K =1.3 and 1.9 nm), high σ /σ selectivity (>1500-fold), low lipophilicity (logD =1.8) and very good ligand efficiency (LELP=5.5), indicating promising pharmacodynamics and pharmacokinetics. Molecular simulation studies, including docking and deconvolution of the free binding energy into its major components, led to decreased hydrophobic stabilization of pyridyl derivatives 33 c and 34 c, which was compensated by lower desolvation energy.

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“…In particular, compounds 1a (H) and 1d showed the most interesting σ1R affinity within this molecular series, with K i σ 1 values of 2.6 nM and 7.1 nM and selectivity ratio (K i σ 2 /K i σ 1 ) of 46.2 and 5.1, respectively. Encouraged by these results, we then selected some of these molecules as training/test set compounds for the construction of a three-dimensional (3D) pharmacophore model for σ1R binding [17], and the subsequent original development of a σ1R 3D homology model [18], extensively validated in successive works [19][20][21][22][23][24][25][26][27][28]. The information retrieved from the combined application of 3D pharmacophore modeling and molecular dynamics (MD)-based docking and scoring calculations using the 3D σ1R homology model allowed us to fully characterize the network of intermolecular interactions responsible for the potency of compounds 1 as σ1R binders.…”

Section: Introductionmentioning

confidence: 99%

Computer-assisted design, synthesis, binding and cytotoxicity assessments of new 1-(4-(aryl(methyl)amino)butyl)-heterocyclic sigma 1 ligands

Zampieri

Vio

Fermeglia

et al. 2016

European Journal of Medicinal Chemistry

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In this work we applied a blend of computational and synthetic techniques with the aim to design, synthesize, and characterize new σ1 receptor (σ1R) ligands. Starting from the structure of previously reported, high-affinity benzoxazolone-based σ1 ligands, the three-dimensional homology model of the σ1R was exploited for retrieving the molecular determinants to fulfill the optimal pharmacophore requirements. Accordingly, the benzoxazolone moiety was replaced by other heterocyclic scaffolds, the relevant conformational space in the σ1R binding cavity was explored, and the effect on σ1R binding affinity was ultimately assessed. Next, the compounds designed in silico were synthesized, and their affinity and selectivity toward σ1 and σ2 receptors were tested. Finally, a representative series of best σ1R binders were assayed for cytotoxic activity on the SH-SY5Y human neuroblastoma cell line. Specifically, the new 4-phenyloxazolidin-2-one derivatives 2b (i.e., (R)-2b and (S)-2b) emerged as potential leads for further development as σ1R agents, as they were found endowed with the highest σ1R affinity (Kiσ1 values in the range 0.95-9.3 nM), and showed minimal cytotoxic levels exhibited in the selected, cell-based test, in line with a σ1R agonist behavior.

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Identification of RC-33 as a potent and selective σ1 receptor agonist potentiating NGF-induced neurite outgrowth in PC12 cells. Part 2: g-Scale synthesis, physicochemical characterization and in vitro metabolic stability

Cited by 37 publications

References 74 publications

Studies on the Enantiomers of RC-33 as Neuroprotective Agents: Isolation, Configurational Assignment, and Preliminary Biological Profile

Studies on the Enantiomers of RC-33 as Neuroprotective Agents: Isolation, Configurational Assignment, and Preliminary Biological Profile

Thiazole‐Based σ₁ Receptor Ligands: Diversity by Late‐Stage C−H Arylation of Thiazoles, Structure–Affinity and Selectivity Relationships, and Molecular Interactions

Computer-assisted design, synthesis, binding and cytotoxicity assessments of new 1-(4-(aryl(methyl)amino)butyl)-heterocyclic sigma 1 ligands

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Identification of RC-33 as a potent and selective σ1 receptor agonist potentiating NGF-induced neurite outgrowth in PC12 cells. Part 2: g-Scale synthesis, physicochemical characterization and in vitro metabolic stability

Cited by 37 publications

References 74 publications

Studies on the Enantiomers of RC-33 as Neuroprotective Agents: Isolation, Configurational Assignment, and Preliminary Biological Profile

Studies on the Enantiomers of RC-33 as Neuroprotective Agents: Isolation, Configurational Assignment, and Preliminary Biological Profile

Thiazole‐Based σ1 Receptor Ligands: Diversity by Late‐Stage C−H Arylation of Thiazoles, Structure–Affinity and Selectivity Relationships, and Molecular Interactions

Computer-assisted design, synthesis, binding and cytotoxicity assessments of new 1-(4-(aryl(methyl)amino)butyl)-heterocyclic sigma 1 ligands

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Product

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Thiazole‐Based σ₁ Receptor Ligands: Diversity by Late‐Stage C−H Arylation of Thiazoles, Structure–Affinity and Selectivity Relationships, and Molecular Interactions