Identification of a potent and selective σ1 receptor agonist potentiating NGF-induced neurite outgrowth in PC12 cells

Rossi, Daniela; Pedrali, Alice; Urbano, Mariangela; Gaggeri, Raffaella; Serra, Massimo; Fernández, Leyden; Fernández, Michael; Caballero, Julio; Ronsisvalle, Simone; Prezzavento, Orazio; Schepmann, Dirk; Wuensch, B.; Peviani, Marco; Curti, Daniela; Azzolina, Ornella; Collina, Simona

doi:10.1016/j.bmc.2011.09.016

Cited by 45 publications

(27 citation statements)

References 35 publications

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“…[α] D 20 = + 18.3 ( c 0.5, CHCl 3 ). Spectroscopic properties comply with those reported in the literature . HPLC (Table ): t Rminor = 5.36 min, t Rmajor = 5.91 min.…”

Section: Methodssupporting

confidence: 85%

“…In our compound library, the most promising molecule is rac ‐1‐[3‐(1,1'‐biphen)‐4‐yl]butyl‐piperidine · HCl ( rac ‐ RC-33 · HCl, Fig. ), 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) .…”

Section: Introductionmentioning

confidence: 99%

“…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%

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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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“…[α] D 20 = + 18.3 ( c 0.5, CHCl 3 ). Spectroscopic properties comply with those reported in the literature . HPLC (Table ): t Rminor = 5.36 min, t Rmajor = 5.91 min.…”

Section: Methodssupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

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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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“…We evaluated the immunomodulatory actions of increasing doses of σ ligands on the production of IL-2 and TNFα by activated Jurkat cells. Both selective σ-1 agonist PRE-084 ( K i values of 2.2 and 13091 nM for σ-1 and σ-2 receptors respectively; Su et al, 1991; Rossi et al, 2011) and σ-1 antagonist BD-1063 ( K i value of 9 nM for the σ-1 receptor and more than 49 times selectivity over the σ-2 receptor; Matsumoto et al, 1995; Entrena et al, 2009), were used to determine the effect of σ-1 ligands in these cells. As shown in Figure 2, neither the σ-1 agonist PRE-084 nor the σ-1 antagonist BD-1063 showed a significant effect on the induction of the production of IL-2 or TNFα in Jurkat T cells upon stimulation with PMA + Ion.…”

Section: Resultsmentioning

confidence: 99%

Inhibitory Effects of Sigma-2 Receptor Agonists on T Lymphocyte Activation

Íñiguez¹,

Punzón²,

Nieto³

et al. 2013

Front. Pharmacol.

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Sigma (σ) receptor ligands are essentially known for their effects on the nervous system although recent studies have shown their potential effects modulating some other pathophysiological processes as cell proliferation, cancer, and the immune response. Here, we have analyzed the actions of σ-1 and σ-2 receptors ligands on T cell activation. Our results show that treatment of Jurkat T cells with σ-2 agonists decreased the induction of the expression of Interleukin (IL)-2, Tumor necrosis factor (TNF)-α, and Cyclooxygenase (COX)-2 by activated T cells in a dose-dependent manner. These effects take place at the transcriptional level since σ-2 agonists BD-737 and CB-184 diminished the activity of the promoters of those genes. Those immunosuppressive effects could be attributable to interference with transcription factor activation. Induced transcription mediated by Nuclear factor (NF)-κB or Nuclear Factor of Activated T cells (NFAT) was inhibited by σ-2 agonists. These effects seem to be specific for σ-2 agonists as no significant effects on T cell activation by σ-1 ligands PRE-084 and BD-1063 were found. Our results provide new insights into the immunomodulatory actions of σ ligands and describe a new property of σ-2 agonists, through inhibition of activation of transcription factors as NFAT by which these compounds are regulating gene expression. This may have important consequences on the possible therapeutic use of those compounds.

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“…Sigma-1 receptors activate tropomycin receptor kinase, a family of neurotrophin receptors which promotes neuroplasticity [113]. Receptor agonists stimulate neurite outgrowth while antagonists block neurite formation stimulated by nerve growth factor [114][115][116][117].…”

Section: Biologic Effects Of Sigma-1 Receptorsmentioning

confidence: 99%

Sigma-1 receptors and animal studies centered on pain and analgesia

Davis

2015

Expert Opinion on Drug Discovery

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Sigma-1 receptor antagonists have a great potential as analgesics for acute neuropathic injury (herpes zoster, acute postoperative pain and chemotherapy induced neuropathy) and may, as an additional benefit, prevent the development of chronic neuropathic pain. Antagonists are potentially effective as adjuvants to opioid therapy when used early to prevent analgesic tolerance. Drug development is complicated by the complexity of sigma-1 receptor pharmacodynamics and its multiple targets, the lack of a specific sigma-1 receptor antagonist, and potential side effects due to on-target toxicities (cognitive impairment, depression).

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Identification of a potent and selective σ1 receptor agonist potentiating NGF-induced neurite outgrowth in PC12 cells

Cited by 45 publications

References 35 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

Inhibitory Effects of Sigma-2 Receptor Agonists on T Lymphocyte Activation

Sigma-1 receptors and animal studies centered on pain and analgesia

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