A Group of Potassium-Channel Blockers-Acetylcholine Releasers
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This review of the literature examines systematically the data currently available for potassium-channel blockers to reassess their clinical potential in Alzheimer disease. The conclusion is that potassium-channel blockers may have been dismissed prematurely for the treatment of Alzheimer disease, an impression supported by data indicating intimate relationships between potassium-channel blockade and cholinergic transmission.Keywords:
Potassium channel blocker
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Shaker
Potassium channel blocker
Voltage-gated potassium channel
Unconsciousness
Homomeric
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The Kv1.5 potassium channel provides an ultra-rapid delayed rectifier potassium current, I Kur , that acts selectively in human atrial cells. This makes selective Kv1.5 blockade a promising approach to control atrial arrhythmias without the adverse ventricular effects associated with classical hERG-subtype potassium channel blockers (Kv11.1). This review considers all currently known Kv1.5-channel blockers with a biaromatic structure and data on their biological properties. For many of the Kv1.5-selective compounds studied, the ability to prevent the development of atrial arrhythmias without affecting ventricular refractoriness was confirmed.
hERG
Potassium channel blocker
Channel blocker
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The ability to directly measure acetylcholine (ACh) release is an essential first step towards understanding its physiological function. Here we optimized the GRAB ACh ( G PC R - A ctivation– B ased- ACh ) sensor with significantly improved sensitivity and minimal downstream coupling. Using this sensor, we measured in-vivo cholinergic activity in both Drosophila and mice, revealing compartmental ACh signals in fly olfactory center and single-trial ACh dynamics in multiple regions of the mice brain under a variety of different behaviors
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There has been an increasing interest in compounds that modulate potassium ion channels (K+-channels) since they can be developed as important therapeutic agents against ischemic heart diseases. Of the diverse family of K+- channels, the voltage-gated potassium channel Kv1.3 constitutes an attractive target for the selective suppression of effector memory T cells in autoimmune diseases. For the development of antiarrythmic drugs, the blockade of the rapidly activating delayed rectifier (IKr) and slowly activating delayed rectifier (IKs) potassium currents has been specifically studied. Since the discovery of IKs-channel, its blockers have been particularly more studied. In this communication, we present QSAR studies on a few series of Kv1.3-channel blockers and a series of IKs-channel blockers in order to provide some guidelines to the drug development. Keywords: Quantitative structure-activity relationship study, potassium channel blockers, Kv1.3-channel blockers, IKschannel blockers, khellinone analogs, chromanols
Potassium channel blocker
Channel blocker
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Abstract The transmission of impulses throughout the cholinergic nervous system is mediated by acetylcholine, and compounds that produce their pharmacologic effects by mimicking or substituting for acetylcholine are called cholinergics or parasympathomimetics. Compounds that inhibit or inactivate the body's normal hydrolysis of acetylcholine by acetylcholinesterase in nervous tissue and/or by butyrylcholinesterase (pseudocholinesterase, cholinesterase) in the plasma are called anticholinesterases. The gross observable pharmacological effects of both types of compounds are quite similar. More recently, compounds have been found that enhance the release of acetylcholine from cholinergic nerve terminals, thus (like the anticholinesterases) producing cholinergic effects by an indirect mechanism. These concepts are discussed in this chapter.
Cholinesterase
Butyrylcholinesterase
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The potassium channels were recently found to be inhibited by animal toxin-like human β-defensin 2 (hBD2), the first defensin blocker of potassium channels. Whether there are other defensin blockers from different organisms remains an open question. Here, we reported the potassium channel-blocking plectasin, the first defensin blocker from a fungus. Based on the similar cysteine-stabilized alpha-beta (CSαβ) structure between plectasin and scorpion toxins acting on potassium channels, we found that plectasin could dose-dependently block Kv1.3 channel currents through electrophysiological experiments. Besides Kv1.3 channel, plectasin could less inhibit Kv1.1, Kv1.2, IKCa, SKCa3, hERG and KCNQ channels at the concentration of 1 μΜ. Using mutagenesis and channel activation experiments, we found that outer pore region of Kv1.3 channel was the binding site of plectasin, which is similar to the interacting site of Kv1.3 channel recognized by animal toxin blockers. Together, these findings not only highlight the novel function of plectasin as a potassium channel inhibitor, but also imply that defensins from different organisms functionally evolve to be a novel kind of potassium channel inhibitors.
Potassium channel blocker
hERG
SK channel
Channel blocker
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On the basis of the data obtained during a determination of the cholinergic blood activity in different physiological and pathological conditions of the organism it was possible to evaluate the state (tone and reactivity) of the parasympathetic part of the vegetative nervous system. The conducted studies demonstrate that the cholinergic blood activity depends upon the quantitative relationships between the separate components of the "acetylcholine system" which consists of the free acetylcholine content, bound erythrocytes, the activity of the acetylcholine esterase and the capability of blood in vitro to fixate the added acetylcholine. The pathogenetic therapy in the different forms of disturbed cholinergic blood activity (conditions of parasympathicotonia and parasympathicoatonia) should be directed to a restitution of normal relationships within the acetylcholine complex.
Parasympathetic nervous system
Cholinesterase
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It is well known that acetylcholine represents a dominant neurotransmitter within mammalian airways and that airway functions, like smooth muscle activity and secretion, are under a continuous cholinergic tone. However, the teleology of this basal cholinergic tone, assumed to originate from neuronal activity, appears difficult to understand, whereas neuronal cholinergic reflex activity can be regarded as a rational regulatory pathway to protect the airways from injury [-]. Based on recent experimental observations, both phenomena may reflect two different biological roles of acetylcholine, acting first as a universal cytomolecule (non-neuronal) and second as a classical neurotransmitter (neuronal).
Premovement neuronal activity
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