Novel compounds with dual S1P receptor agonist and histamine H3 receptor antagonist activities act protective in a mouse model of multiple sclerosis

Imeri, Faik; Tanturovska, Bisera Stepanovska; Živković, Aleksandra; Enzmann, Gaby; Schwalm, Stephanie; Pfeilschifter, Josef; Homann, Thomas; Kleuser, Burkhard; Engelhardt, Britta; Stark, Holger; Huwiler, Andrea

doi:10.1016/j.neuropharm.2021.108464

Cited by 16 publications

(9 citation statements)

References 56 publications

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“… 9 − 11 With the recent market approval of pitolisant (Wakix), the interest in clinical applications of novel multifunctional H 3 R antagonists has clearly increased. 12 − 16 Interestingly, the latest studies have shown that some clinically evaluated H 3 R receptor antagonists possess nanomolar affinity at sigma-1 receptor (σ 1 R) binding sites, suggesting that this feature might play an essential role in their overall efficacy ( Figure 1 ). 17 − 19 This discovery may be a breakthrough in the therapeutic use of these compounds and opens a brand-new research area in the search for novel drugs.…”

Section: Introductionmentioning

confidence: 99%

“…Histamine H 3 receptors (H 3 Rs) belong to the family of G-protein-coupled receptors (GPCRs) and provide a broad spectrum of neuromodulatory functions in the CNS . They have been described as both presynaptic autoreceptors regulating the synthesis and release of histamine and heteroreceptors modulating the release of neurotransmitters such as acetylcholine, dopamine, norepinephrine, serotonin, γ-aminobutyric acid, glutamate, and substance P. , Pharmacological data reveal potentially beneficial outcomes of H 3 R antagonists or inverse agonists for the treatment of schizophrenia, Alzheimer’s and Parkinson’s diseases, obesity, narcolepsy, and attention-deficit hyperactivity disorder (ADHD), also as multitargeting ligands. − With the recent market approval of pitolisant (Wakix), the interest in clinical applications of novel multifunctional H 3 R antagonists has clearly increased. − Interestingly, the latest studies have shown that some clinically evaluated H 3 R receptor antagonists possess nanomolar affinity at sigma-1 receptor (σ 1 R) binding sites, suggesting that this feature might play an essential role in their overall efficacy (Figure ). − This discovery may be a breakthrough in the therapeutic use of these compounds and opens a brand-new research area in the search for novel drugs …”

Section: Introductionmentioning

confidence: 99%

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Structural and Molecular Insight into Piperazine and Piperidine Derivatives as Histamine H₃ and Sigma-1 Receptor Antagonists with Promising Antinociceptive Properties

Szczepańska

Podlewska

Dichiara

et al. 2021

ACS Chem. Neurosci.

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In an attempt to extend recent studies showing that some clinically evaluated histamine H 3 receptor (H 3 R) antagonists possess nanomolar affinity at sigma-1 receptors (σ 1 R), we selected 20 representative structures among our previously reported H 3 R ligands to investigate their affinity at σRs. Most of the tested compounds interact with both sigma receptors to different degrees. However, only six of them showed higher affinity toward σ 1 R than σ 2 R with the highest binding preference to σ 1 R for compounds 5 , 11 , and 12 . Moreover, all these ligands share a common structural feature: the piperidine moiety as the fundamental part of the molecule. It is most likely a critical structural element for dual H 3 /σ 1 receptor activity as can be seen by comparing the data for compounds 4 and 5 (hH 3 R K i = 3.17 and 7.70 nM, σ 1 R K i = 1531 and 3.64 nM, respectively), where piperidine is replaced by piperazine. We identified the putative protein–ligand interactions responsible for their high affinity using molecular modeling techniques and selected compounds 5 and 11 as lead structures for further evaluation. Interestingly, both ligands turned out to be high-affinity histamine H 3 and σ 1 receptor antagonists with negligible affinity at the other histamine receptor subtypes and promising antinociceptive activity in vivo . Considering that many literature data clearly indicate high preclinical efficacy of individual selective σ 1 or H 3 R ligands in various pain models, our research might be a breakthrough in the search for novel, dual-acting compounds that can improve existing pain therapies. Determining whether such ligands are more effective than single-selective drugs will be the subject of our future studies.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Structural and Molecular Insight into Piperazine and Piperidine Derivatives as Histamine H₃ and Sigma-1 Receptor Antagonists with Promising Antinociceptive Properties

Szczepańska

Podlewska

Dichiara

et al. 2021

ACS Chem. Neurosci.

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“…Moreover, Epo in mouse plasma was also enhanced in Sphk2−/− ( Figure 7 D). To see whether this has a consequence on the number of red blood cells in Sphk2−/− mice, we re-analyzed the red blood cells and the hemoglobin level from our previous studies on Sphk2−/− where we had determined lymphocyte numbers [ 52 , 53 , 54 ]. Retrospectively, data from 22 Wt mice and 23 Sphk2−/− mice were pooled and show increased hemoglobin and a trend to increased red blood cells in Sphk2−/− ( Figure 7 E,F).…”

Section: Resultsmentioning

confidence: 99%

Sphk1 and Sphk2 Differentially Regulate Erythropoietin Synthesis in Mouse Renal Interstitial Fibroblast-like Cells

Hafizi

Imeri

Tanturovska

et al. 2022

IJMS

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Erythropoietin (Epo) is a crucial hormone regulating red blood cell number and consequently the hematocrit. Epo is mainly produced in the kidney by interstitial fibroblast-like cells. Previously, we have shown that in cultures of the immortalized mouse renal fibroblast-like cell line FAIK F3-5, sphingosine 1-phosphate (S1P), by activating S1P1 and S1P3 receptors, can stabilize hypoxia-inducible factor (HIF)-2α and upregulate Epo mRNA and protein synthesis. In this study, we have addressed the role of intracellular iS1P derived from sphingosine kinases (Sphk) 1 and 2 on Epo synthesis in F3-5 cells and in mouse primary cultures of renal fibroblasts. We show that stable knockdown of Sphk2 in F3-5 cells increases HIF-2α protein and Epo mRNA and protein levels, while Sphk1 knockdown leads to a reduction of hypoxia-stimulated HIF-2α and Epo protein. A similar effect was obtained using primary cultures of renal fibroblasts isolated from wildtype mice, Sphk1−/−, or Sphk2−/− mice. Furthermore, selective Sphk2 inhibitors mimicked the effect of genetic Sphk2 depletion and also upregulated HIF-2α and Epo protein levels. The combined blockade of Sphk1 and Sphk2, using Sphk2−/− renal fibroblasts treated with the Sphk1 inhibitor PF543, resulted in reduced HIF-2α and Epo compared to the untreated Sphk2−/− cells. Exogenous sphingosine (Sph) enhanced HIF-2α and Epo, and this was abolished by the combined treatment with the selective S1P1 and S1P3 antagonists NIBR-0213 and TY52156, suggesting that Sph was taken up by cells and converted to iS1P and exported to then act in an autocrine manner through S1P1 and S1P3. The upregulation of HIF-2α and Epo synthesis by Sphk2 knockdown was confirmed in the human hepatoma cell line Hep3B, which is well-established to upregulate Epo production under hypoxia. In summary, these data show that sphingolipids have diverse effects on Epo synthesis. While accumulation of intracellular Sph reduces Epo synthesis, iS1P will be exported to act through S1P1+3 to enhance Epo synthesis. Furthermore, these data suggest that selective inhibition of Sphk2 is an attractive new option to enhance Epo synthesis and thereby to reduce anemia development in chronic kidney disease.

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“…Molecular modelling, energy minimization experiments and dynamics simulations were performed as previously explained [ 33 ].…”

Section: Methodsmentioning

confidence: 99%

ST-2191, an Anellated Bismorpholino Derivative of Oxy-Fingolimod, Shows Selective S1P1 Agonist and Functional Antagonist Potency In Vitro and In Vivo

et al. 2021

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Sphingosine 1-phosphate (S1P) is an extensively studied signaling molecule that contributes to cell proliferation, survival, migration and other functions through binding to specific S1P receptors. The cycle of S1P1 internalization upon S1P binding and recycling to the cell surface when local S1P concentrations are low drives T cell trafficking. S1P1 modulators, such as fingolimod, disrupt this recycling by inducing persistent S1P1 internalization and receptor degradation, which results in blocked egress of T cells from the secondary lymphoid tissues. The approval of these compounds for the treatment of multiple sclerosis has placed the development of S1PR modulators in the focus of pharmacological research, mostly for autoimmune indications. Here, we report on a novel anellated bismorpholino derivative of oxy-fingolimod, named ST-2191, which exerts selective S1P1 agonist and functional antagonist potency. ST-2191 is also effective in reducing the lymphocyte number in mice, and this effect is not dependent on phosphorylation by sphingosine kinase 2 for activity. These data show that ST-2191 is a novel S1P1 modulator, but further experiments are needed to analyze the therapeutic impact of ST-2191 in animal models of autoimmune diseases.

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Novel compounds with dual S1P receptor agonist and histamine H3 receptor antagonist activities act protective in a mouse model of multiple sclerosis

Cited by 16 publications

References 56 publications

Structural and Molecular Insight into Piperazine and Piperidine Derivatives as Histamine H₃ and Sigma-1 Receptor Antagonists with Promising Antinociceptive Properties

Structural and Molecular Insight into Piperazine and Piperidine Derivatives as Histamine H₃ and Sigma-1 Receptor Antagonists with Promising Antinociceptive Properties

Sphk1 and Sphk2 Differentially Regulate Erythropoietin Synthesis in Mouse Renal Interstitial Fibroblast-like Cells

ST-2191, an Anellated Bismorpholino Derivative of Oxy-Fingolimod, Shows Selective S1P1 Agonist and Functional Antagonist Potency In Vitro and In Vivo

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Novel compounds with dual S1P receptor agonist and histamine H3 receptor antagonist activities act protective in a mouse model of multiple sclerosis

Cited by 16 publications

References 56 publications

Structural and Molecular Insight into Piperazine and Piperidine Derivatives as Histamine H3 and Sigma-1 Receptor Antagonists with Promising Antinociceptive Properties

Structural and Molecular Insight into Piperazine and Piperidine Derivatives as Histamine H3 and Sigma-1 Receptor Antagonists with Promising Antinociceptive Properties

Sphk1 and Sphk2 Differentially Regulate Erythropoietin Synthesis in Mouse Renal Interstitial Fibroblast-like Cells

ST-2191, an Anellated Bismorpholino Derivative of Oxy-Fingolimod, Shows Selective S1P1 Agonist and Functional Antagonist Potency In Vitro and In Vivo

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Structural and Molecular Insight into Piperazine and Piperidine Derivatives as Histamine H₃ and Sigma-1 Receptor Antagonists with Promising Antinociceptive Properties

Structural and Molecular Insight into Piperazine and Piperidine Derivatives as Histamine H₃ and Sigma-1 Receptor Antagonists with Promising Antinociceptive Properties