The Concise Guide to PHARMACOLOGY 2015/16: Other ion channels

Alexander, Stephen P.H.; Kelly, Eamonn; Marrion, Neil V.; Peters, John A.; Benson, Helen E.; Faccenda, Elena; Pawson, Adam J.; Sharman, Joanna L.; Southan, Christopher; Davies, Jamie A.

doi:10.1111/bph.13351

Cited by 45 publications

(25 citation statements)

References 13 publications

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“…Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Harding et al, ), and are permanently archived in the Concise Guide to PHARMACOLOGY 2019/20 (Alexander, Fabbro et al, ; Alexander, Kelly et al, ).…”

Section: Methodsmentioning

confidence: 99%

PO‐322 exerts potent immunosuppressive effects in vitro and in vivo by selectively inhibiting SGK1 activity

Lai

Luo

Guo

et al. 2020

British J Pharmacology

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Background and Purpose Immunosuppressive drugs have shown great promise in treating autoimmune diseases in recent years. A series of novel oxazole derivatives were screened for their immunosuppressive activity. PO‐322 [1H‐indole‐2,3‐dione 3‐(1,3‐benzoxazol‐2‐ylhydrazone)] was identified as the most effective of these compounds. Here, we have investigated the mechanism(s) underlying the inhibition of T‐cell proliferation in vitro by PO‐322, as well as its effects on the delayed‐type hypersensitivity (DTH) response and imiquimod‐induced dermatitis in vivo. Experimental Approach T‐cell proliferation and apoptosis were analysed with flow cytometry. Cell viability was assessed with a CCK‐8 assay. Protein kinase activity was assessed by SelectScreen Kinase Profiling Services. The phosphorylation of signal‐regulated molecules was measured by Western blot. Cytokine levels were determined by elisa. The effect of PO‐322 on DTH and imiquimod‐induced dermatitis was evaluated in BALB/c mice. Key Results PO‐322 inhibited human T‐cell proliferation with anti‐CD3/anti‐CD28 mAbs or alloantigen without significant cytotoxicity. Importantly, PO‐322 was a selective inhibitor of the serum‐ and glucocorticoid‐regulated kinase 1 (SGK1) and decreased NDRG1 phosphorylation but not p70S6K, STAT5, Akt, or ERK1/2 phosphorylation. Furthermore, PO‐322 inhibited IFN‐γ, IL‐6, and IL‐17 expression but not IL‐10 expression. Finally, treatment with PO‐322 was safe and effective for ameliorating the DTH response and imiquimod‐induced dermatitis in mice. Conclusions and Implications PO‐322 exerted immunosuppressive activity in vitro and in vivo by selectively inhibiting SGK1 activity. PO‐322 represents a potential lead compound for the design and development of new drugs for the treatment of autoimmune diseases.

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Section: Methodsmentioning

confidence: 99%

PO‐322 exerts potent immunosuppressive effects in vitro and in vivo by selectively inhibiting SGK1 activity

Lai

Luo

Guo

et al. 2020

British J Pharmacology

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Section: Methodsmentioning

confidence: 99%

Identification, preclinical profile, and clinical proof of concept of an orally bioavailable pro‐drug of miridesap

Richards

Bamford

Liefaard

et al. 2020

British J Pharmacology

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Background and Purpose Miridesap, a depleter of serum amyloid P component (SAP), forms an essential component of a novel approach to remove systemic amyloid deposits; low oral bioavailability necessitates that it is given parenterally. We sought to identify and clinically characterise a pro‐drug that preserves the pharmacological properties of miridesap while having adequate oral bioavailability and physical stability. Experimental Approach We utilised a preclinical screening cascade focused on appropriate physicochemical properties, physical and gut stability, and conversion to miridesap in liver microsomes and blood. GSK3039294 (GSK294) had the desired in vitro profile and progressed to preclinical in vivo pharmacokinetic and safety assessments. Based on a favourable profile, it was tested in healthy participants after single and repeat dosing. Key Results GSK294 was highly soluble and stable in simulated gastric and intestinal fluids, stable in intestinal microsomes, and permeable in Madine Darby Canine Kidney type II cells. GSK294 was rapidly hydrolysed to miridesap and its mono pro‐drug ester in blood and liver microsomes. GSK294 showed good oral bioavailability of miridesap in rats and dogs. Following administration of GSK294 600 mg QD for 7 days in humans, pharmacodynamically active concentrations of miridesap were achieved with substantial and sustained depletion of plasma SAP. The study was terminated due to observations of arrhythmia, the relation of which to GSK294 remains unclear. Conclusion and Implications Using a preclinical screening cascade, we identified a pro‐drug for a palindromic molecule with unique pharmacology (miridesap). The pro‐drug depleted circulating SAP with a time course and extent similar to that of parenterally administered miridesap.

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“…In non-excitable tissue, ion channels regulate important biological functions such as epithelial transport of nutrients and ions, T-cell activation in inflammatory processes and release of insulin by pancreatic β-cells. It has been well established that most Na + , K + , Ca 2+ and some Cl channels, are voltage-gated [61] but others including certain K + and Cl − channels, transient receptor potential (TRP) channels, ryanodine receptors and IP 3 receptors, are relatively voltage-insensitive and are gated by second messengers and other intracellular and/or extracellular mediators [62]. Voltage-gated ion channels (Figure 1 portal 2) open or close depending on the voltage gradient across the plasma membrane.…”

Section: Toxins and Their Target Of Actionmentioning

confidence: 99%

“…The molecule is a strong excitatory neurotoxin, that following systemic or intracerebral administration generates seizure in rodents. The targets of KA, the iGluRs, are classified into three subtypes according to the compounds that preferentially activate them: AMPA (2-amino-3-hydroxy-5-methylisoxazole propionic acid), NMDA ( N -methyl- d - aspartate) and KA [62]. Within these subclasses, multiple subunits have been identified.…”

Section: Toxins and Their Target Of Actionmentioning

confidence: 99%

“…As found for AMPA receptors, kainate receptors are modulated by auxiliary subunits. An important functional difference between AMPA and kainate receptors is that the latter require extracellular Na + and Cl − ions for their activation [62]. However, KA also activates the AMPA receptors, which are composed of subunits GluR1-4, even if with lower affinity [183].…”

Section: Toxins and Their Target Of Actionmentioning

confidence: 99%

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The Molecular Basis of Toxins’ Interactions with Intracellular Signaling via Discrete Portals

Lahiani

Yavin

Lazarovici

2017

Toxins

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An understanding of the molecular mechanisms by which microbial, plant or animal-secreted toxins exert their action provides the most important element for assessment of human health risks and opens new insights into therapies addressing a plethora of pathologies, ranging from neurological disorders to cancer, using toxinomimetic agents. Recently, molecular and cellular biology dissecting tools have provided a wealth of information on the action of these diverse toxins, yet, an integrated framework to explain their selective toxicity is still lacking. In this review, specific examples of different toxins are emphasized to illustrate the fundamental mechanisms of toxicity at different biochemical, molecular and cellular- levels with particular consideration for the nervous system. The target of primary action has been highlighted and operationally classified into 13 sub-categories. Selected examples of toxins were assigned to each target category, denominated as portal, and the modulation of the different portal’s signaling was featured. The first portal encompasses the plasma membrane lipid domains, which give rise to pores when challenged for example with pardaxin, a fish toxin, or is subject to degradation when enzymes of lipid metabolism such as phospholipases A2 (PLA2) or phospholipase C (PLC) act upon it. Several major portals consist of ion channels, pumps, transporters and ligand gated ionotropic receptors which many toxins act on, disturbing the intracellular ion homeostasis. Another group of portals consists of G-protein-coupled and tyrosine kinase receptors that, upon interaction with discrete toxins, alter second messengers towards pathological levels. Lastly, subcellular organelles such as mitochondria, nucleus, protein- and RNA-synthesis machineries, cytoskeletal networks and exocytic vesicles are also portals targeted and deregulated by other diverse group of toxins. A fundamental concept can be drawn from these seemingly different toxins with respect to the site of action and the secondary messengers and signaling cascades they trigger in the host. While the interaction with the initial portal is largely determined by the chemical nature of the toxin, once inside the cell, several ubiquitous second messengers and protein kinases/ phosphatases pathways are impaired, to attain toxicity. Therefore, toxins represent one of the most promising natural molecules for developing novel therapeutics that selectively target the major cellular portals involved in human physiology and diseases.

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The Concise Guide to PHARMACOLOGY 2015/16: Other ion channels

Cited by 45 publications

References 13 publications

PO‐322 exerts potent immunosuppressive effects in vitro and in vivo by selectively inhibiting SGK1 activity

PO‐322 exerts potent immunosuppressive effects in vitro and in vivo by selectively inhibiting SGK1 activity

Identification, preclinical profile, and clinical proof of concept of an orally bioavailable pro‐drug of miridesap

The Molecular Basis of Toxins’ Interactions with Intracellular Signaling via Discrete Portals

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