Abstract:Given their many physiological functions, K(ATP) channels represent promising drug targets. Sulfonylureas like glibenclamide block K(ATP) channels; they are used in the therapy of type 2 diabetes. Openers of K(ATP) channels (KCOs) e.g. relax smooth muscle and induce hypotension. KCOs are chemically heterogeneous and include as different classes as the benzopyrans, cyanoguanidines, thioformamides, thiadiazines and pyridyl nitrates. Examples for new chemical entities more recently developed as KCOs include cyclo… Show more
“…Interestingly, a clinical trial for T2D with the IL-1R antagonist anakinra has shown some promise, as anakinra improved glycemia and beta-cell secretory function, and reduced markers of systemic inflammation. 81 Furthermore, the common anti-diabetic drug, glibenclamide (also known as glyburide), which operates by inhibiting ATP-sensitive potassium channels, 82 was shown to inhibit NLRP3 inflammasome assembly and caspase-1 activation, suggesting that pharmacological modulation of the inflammasome-IL-1b axis might be a viable approach for the treatment of T2D. 83 A second drug most commonly used for the treatment of T2D is metformin, which acts by activating AMPK and the upstream kinase LKB1 (reviewed in Hardie 84 ), arguing that its efficacy might be partially mediated by modulating inflammasome activity.…”
Section: The Inflammasome and The Metabolic Syndromementioning
A decade ago, Jurg Tschopp introduced the concept of the inflammasome. This exciting discovery of a macromolecular complex that senses 'danger' and initiates the inflammatory response contributed to a renaissance in the fields of innate immunity and cell death. Jurg led the biochemical characterization of the inflammasome complex and demonstrated that spontaneous hyperactivation of this interleukin (IL)-1b processing machinery is the molecular basis of a spectrum of hereditary periodic fever syndromes, caused by mutated forms of the inflammasome scaffolding receptor, NLRP3. The identification of the underlying mechanism in these disorders has led to their now successful therapy, with the use of the IL-1 receptor antagonist in the clinic. Jurg's pioneering work has subsequently defined a number of inflammasome agonists ranging from microbial molecules expressed during infection, to triggers of sterile inflammation, most notably gout-associated uric acid crystals, asbestos, silica and nanoparticles. More recently, Jurg introduced the critical new concept of the metabolic inflammasome, which senses metabolic stress and contributes to the onset of the metabolic syndrome associated with obesity and type 2 diabetes. Jurg was an outstanding and skillful biochemist, an elegant and rigorous researcher often far ahead of his peers. He was a truly amiable person, fair, generous and inspiring, and will be most remembered for his infectious enthusiasm. We write this review article on the inflammasome in his honor and dedicate it to his memory. Cell Death and Differentiation (2012) 19, 5-12; doi:10.1038/cdd.2011.159; published online 11 November 2011Facts Tschopp and colleagues discovered the inflammasome platforms and described its biochemistry and clinical relevance in cold-associated periodic syndromes (CAPS) or cryopyrinopathies, gout and type 2 diabetes. Tschopp and colleagues identified a number of inflammasome agonists, namely muramyl dipeptide (MDP), viral DNA, monosodium urate (MSU) crystals, asbestos, silica, alum and malaria-associated hemozoin. Tschopp and colleagues showed that the immunosuppressive function of type I interferon was accomplished through inhibition of the NLRP3 inflammasome. Tschopp and coworkers demonstrated a role of the NLRP3 inflammasome in the metabolic syndrome. Tschopp's research led to the establishment of a number of clinical trials for inflammatory diseases, including CAPS, gout and type 2 diabetes.
Open QuestionsWhat is the molecular mechanism that activates the inflammasome? What is the link between inflammation and cell death pathways, and how does the cell decide to engage one but not the other?Although the role of the inflammasome has been well demonstrated in monogenic inflammatory diseases, what is its role in more complex diseases, and what are the potential therapeutic solutions?Discovery and Molecular Characterization of the Inflammasome Nucleotide-binding domain (NB) and leucine-rich repeat (LRR) containing receptors (NLR), casually referred to as Nod-like receptors, are cytos...
“…Interestingly, a clinical trial for T2D with the IL-1R antagonist anakinra has shown some promise, as anakinra improved glycemia and beta-cell secretory function, and reduced markers of systemic inflammation. 81 Furthermore, the common anti-diabetic drug, glibenclamide (also known as glyburide), which operates by inhibiting ATP-sensitive potassium channels, 82 was shown to inhibit NLRP3 inflammasome assembly and caspase-1 activation, suggesting that pharmacological modulation of the inflammasome-IL-1b axis might be a viable approach for the treatment of T2D. 83 A second drug most commonly used for the treatment of T2D is metformin, which acts by activating AMPK and the upstream kinase LKB1 (reviewed in Hardie 84 ), arguing that its efficacy might be partially mediated by modulating inflammasome activity.…”
Section: The Inflammasome and The Metabolic Syndromementioning
A decade ago, Jurg Tschopp introduced the concept of the inflammasome. This exciting discovery of a macromolecular complex that senses 'danger' and initiates the inflammatory response contributed to a renaissance in the fields of innate immunity and cell death. Jurg led the biochemical characterization of the inflammasome complex and demonstrated that spontaneous hyperactivation of this interleukin (IL)-1b processing machinery is the molecular basis of a spectrum of hereditary periodic fever syndromes, caused by mutated forms of the inflammasome scaffolding receptor, NLRP3. The identification of the underlying mechanism in these disorders has led to their now successful therapy, with the use of the IL-1 receptor antagonist in the clinic. Jurg's pioneering work has subsequently defined a number of inflammasome agonists ranging from microbial molecules expressed during infection, to triggers of sterile inflammation, most notably gout-associated uric acid crystals, asbestos, silica and nanoparticles. More recently, Jurg introduced the critical new concept of the metabolic inflammasome, which senses metabolic stress and contributes to the onset of the metabolic syndrome associated with obesity and type 2 diabetes. Jurg was an outstanding and skillful biochemist, an elegant and rigorous researcher often far ahead of his peers. He was a truly amiable person, fair, generous and inspiring, and will be most remembered for his infectious enthusiasm. We write this review article on the inflammasome in his honor and dedicate it to his memory. Cell Death and Differentiation (2012) 19, 5-12; doi:10.1038/cdd.2011.159; published online 11 November 2011Facts Tschopp and colleagues discovered the inflammasome platforms and described its biochemistry and clinical relevance in cold-associated periodic syndromes (CAPS) or cryopyrinopathies, gout and type 2 diabetes. Tschopp and colleagues identified a number of inflammasome agonists, namely muramyl dipeptide (MDP), viral DNA, monosodium urate (MSU) crystals, asbestos, silica, alum and malaria-associated hemozoin. Tschopp and colleagues showed that the immunosuppressive function of type I interferon was accomplished through inhibition of the NLRP3 inflammasome. Tschopp and coworkers demonstrated a role of the NLRP3 inflammasome in the metabolic syndrome. Tschopp's research led to the establishment of a number of clinical trials for inflammatory diseases, including CAPS, gout and type 2 diabetes.
Open QuestionsWhat is the molecular mechanism that activates the inflammasome? What is the link between inflammation and cell death pathways, and how does the cell decide to engage one but not the other?Although the role of the inflammasome has been well demonstrated in monogenic inflammatory diseases, what is its role in more complex diseases, and what are the potential therapeutic solutions?Discovery and Molecular Characterization of the Inflammasome Nucleotide-binding domain (NB) and leucine-rich repeat (LRR) containing receptors (NLR), casually referred to as Nod-like receptors, are cytos...
“…There are also agents that are able to open K ATP channels [K ATP channel opening drugs (K CO s)]. Intriguingly, not only are some of these agents selective for K ATP but they also exhibit a very broad range of chemical structures: for example, diazoxide is a benzothiadiazine, pinacidil a cyanoguanidine and nicorandil a pyridyl nitrate (Mannhold, ). Agents known to block other K + channels, for example, Ba 2+ and 4‐aminopyridine, are also active on K ATP channels.…”
ATP-sensitive potassium channels (KATP) are widely distributed and present in a number of tissues including muscle, pancreatic beta cells and the brain. Their activity is regulated by adenine nucleotides, characteristically being activated by falling ATP and rising ADP levels. Thus, they link cellular metabolism with membrane excitability. Recent studies using genetically modified mice and genomic studies in patients have implicated KATP channels in a number of physiological and pathological processes. In this review, we focus on their role in cellular function and protection particularly in the cardiovascular system.
AbbreviationsABC, ATP binding cassette; AP, action potential; KATP, ATP-sensitive potassium channel; KCO, ATP-sensitive potassium channel opening drug; PIP2, phosphatidyl 4,5-bisphosphate; SUR, sulphonylurea receptor; VSM, vascular smooth muscle
IntroductionTwo independent laboratories can lay claim to having first described the ATP-sensitive potassium channels (KATP; channel nomenclature follows Alexander et al., 2013). Noma (1983) observed the appearance of an outward K + current in heart muscle cells when treated with metabolic poisons or hypoxia. This was reversed by ATP injected into the cell. Similar observations were made by another group (Trube and Hescheler, 1984). Such channels were subsequently described in pancreatic beta cells (Ashcroft et al., 1984), skeletal muscle (Spruce et al., 1985), smooth muscle (Standen et al., 1989) and neurones (Ashford et al., 1988). During this period, the basic electrophysiological and pharmacological properties of the channel were elucidated (Ashcroft, 1988;Noma and Takano, 1991). In inside-out patches in ∼140 mM symmetrical K + concentrations, the single-channel conductance is ohmic with a conductance of 70-80 pS. The lower values sometimes noted in the literature generally have lower and asymmetric K + concentrations. The channel is highly selective for potassium (PNa/PK∼0.01). Activity is inhibited by the application of ATP with a Ki of 10-500 μM with a Hill coefficient of more than 1 (generally around 2) depending on the tissue and recording configuration. The ATP inhibition is not dependent on ATP hydrolysis: it is not reliant on Mg 2+ and ATP can be substituted by non-hydrolysable derivatives. In the absence of magnesium other adenine nucleotides can inhibit channel activity but they are less potent. However, in the presence of Mg 2+ and ATP, ADP is stimulatory. Even at the beginning of the 1990s the channels were known to have a rich pharmacology (see Edwards and Weston, 1993). Sulphonylureas were discovered accidentally when it was noted that the anti-microbial sulphonamides caused hypoglycaemia in animals. It became apparent that stimulation of insulin release from pancreatic beta cells occurred because of inhibition of KATP channels. There is a family of these drugs: the most widely known are the firstgeneration agents (e.g. tolbutamide, chlorpropamide) and the more potent second-generation agents (e.g. glibenclamide, gliclazide, glipizide). Th...
“…In recent years many structural changes have been made, mainly on the nucleus of benzopyran KCOs, in order to find new compounds with a higher selectivity toward specific targets, such as the K ATP channel of pancreatic β-cells or the cardiac mitochondrial K ATP channel, such as the benzopyranylcyanoguanidine derivatives BMS-180448 and BMS-191095. , Until now, most chemical modifications on benzopyran KCOs have been studied at the C4 position (Figure ), but a few cases have regarded the restriction of the conformation of this substituent through its insertion into a spiro-like structure. 1 Left: graphical representation of SAR data for anti-ischemic properties of benzopyran derivatives, adapted with some modifications from Mannhold . Right: general structure of the synthesized spiromorpholone- ( 1a , b and 2b) and spiromorpholine KCOs ( 3a , b and 4b ).…”
This study was aimed at evaluating, on a limited number of benzopyran compounds, whether the insertion of an electron-rich spirocyclic substituent at the C4 carbon of the benzopyran molecular nucleus may improve the cardioprotective properties against ischemia. Some of the new compounds (1b, 2b, and 4b) exhibited interesting anti-ischemic properties without affecting significantly the blood pressure parameters.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
