Carvedilol blockage of delayed rectifier Kv2.1 channels and its molecular basis

Identification and pharmacological characterization of the voltage‐gated potassium channel Shab in diamondback moth, Plutella xylostella

“…15,23,41 To PxShab, its IC 50 was 11.54 μM, which was close to that of DmShab at +50 mV (11.4 μM). 15 We also tested a series of drugs that may act on mammalian Kv2 channels, including antihypertensive drugs (linoleic acid sodium salt and carvedilol, 24,25 and non-steroidal anti-inflammatory drug celecoxib 23 ). Of these, carvedilol had the best inhibitory effect (IC 50 0.53 μM, Fig.…”

“…These compounds included well-characterized K + channel blockers (tetraethylammonium, 4-aminopyridine, and quinidine) and drugs that may act on mammalian Kv2 channels (linoleic acid sodium salt, celecoxib, and carvedilol). [23][24][25] Pesticides affecting the K + channel were also used in this study. As the botanical insecticide could act on Kv channels, 26 some botanical insecticides, including veratrine, rotenone and azadirachtin (target is still unknown 27 ) were also investigated.…”

“…In this study, we cloned the PxShab gene, studied its electrophysiology and pharmacological properties, and screened a variety of compounds. These compounds included well‐characterized K + channel blockers (tetraethylammonium, 4‐aminopyridine, and quinidine) and drugs that may act on mammalian Kv2 channels (linoleic acid sodium salt, celecoxib, and carvedilol) 23–25 . Pesticides affecting the K + channel were also used in this study.…”

Discovery of 2-Ethoxy-5-isobutyramido-N-1-substituted Benzamide Derivatives as Selective Kv2.1 Inhibitors with In Vivo Neuroprotective Effects

“…One group is the polypeptide molecules isolated from the venom of spiders, scorpions, toads, snakes, and other animals, usually containing 20–60 amino acids, such as Hanatoxin 1, , JZTX, GxTX-1E, and MiDCA1 . Small molecule inhibitors constitute the other group, and most of known small molecule inhibitiors were identified occasionally in pharmacological studies on known drugs, such as the acetylcholinesterase inhibitors galantamine and donepezil, , the antidepressant fluoxetine, the antiarrhythmic drugs flecainide and propafenone, , and the nonselective β-adrenoreceptor antagonist carvedilol . These compounds displayed weak inhibition and poor selectivity toward Kv2.1 while two inhibitors (RY785 and RY796) with high potency and selectivity toward Kv2.1 were discovered through an automated electrophysiological high-throughput screening platform and subsequent strucutrue modifications …”

“…27 Small molecule inhibitors constitute the other group, and most of known small molecule inhibitiors were identified occasionally in pharmacological studies on known drugs, such as the acetylcholinesterase inhibitors galantamine and donepezil, 28,29 the antidepressant fluoxetine, 30 the antiarrhythmic drugs flecainide and propafenone, 31,32 and the nonselective β-adrenoreceptor antagonist carvedilol. 33 These compounds displayed weak inhibition and poor selectivity toward Kv2.1 while two inhibitors (RY785 and RY796) with high potency and selectivity toward Kv2.1 were discovered through an automated electrophysiological high-throughput screening platform and subsequent strucutrue modifications. 34 In our efforts to explore new Kv2.1 inhibitors for the treatment ischemic stroke, we started from RY796 as a template structure, and extensive structure−activity relationships were conducted by variations of substituents on the benzamide scaffold, leading to a series of novel Kv2.1 inhibitors with high potency and selectivity (Figure 1).…”