Potassium channel activator

ANAESTHETICS - GENERAL 2. ANTICANCER AND IMMUNOMODULATING DRUGS -IL-2 3. ANTIDEPRESSANTS - MAOIs 

ANTI HYPERTENSIVES AND HEART FAILURE DRUGS-VASODILATOR ANTI HYPERTENSIVES 

ANXIOLYTICS AND HYPNOTICS 7. BETA-BLOCKERS 8. CALCIUM CHANNEL BLOCKERS 

POTASSIUM CHANNEL ACTIVATORS ALCOHOL Acute alcohol ingestion may t hypotensive effects. Chronic moderate/heavy drinking 1 hypotensive effect 

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Cromakalim (137) is a potassium channel activator commonly used as an antihypertensive agent (107). The rationale for the design of cromakalim is based on P-blockers such as propranolol (115) and atenolol (123). Conformational restriction of the propanolamine side chain as observed in the cromakalim chroman nucleus provides compounds with desired antihypertensive activity free of the side effects commonly associated with P-blockers. Enantiomerically pure cromakalim is produced by resolution of the diastereomeric (T)-a-meth5lben2ylcarbamate derivatives. X-ray crystallographic analysis of this diastereomer provides the absolute stereochemistry of cromakalim. Biological activity resides primarily in the (—)-(33, 4R)-enantiomer [94535-50-9] (137) (108). In spontaneously hypertensive rats, the (—)-(33, 4R)-enantiomer, at dosages of 0.3 mg/kg, lowers the systoHc pressure 47%, whereas the (+)-(3R,43)-enantiomer only decreases the systoHc pressure by 14% at a dose of 3.0 mg/kg. 

Inhibition of voltage operated potassium channels Activation of PLCp... 

Activation of inwardly rectifying potassium channels Activation of MAP kinase... 

YI BA, Minor Jr., Lin Y-F et al (2001) Controlling potassium channel activities interplay between the membrane and intracellular factors. Proc Natl Acad Sci USA 98 11016-11023... 

Azide 367 is prepared from 4-r -butyl-2-nitroaniline in 76% yield by its diazotization followed by treatment with sodium azide. In a 1,3-dipolar cycloaddition with cyanoacetamide, azide 367 is converted to triazole 368 that without separation is directly subjected to Dimroth rearrangement to give derivative 369 in 46% yield. Reduction of the nitro group provides ortfc-phenylenediamine 371 in 91% yield <2000EJM715>. Cyclocondensation of diamine 371 with phosgene furnishes benzimidazol-2-one 370 in 39% yield, whereas its reaction with sodium nitrite in 18% HC1 leads to benzotriazole derivative 372, which is isolated in 66% yield (Scheme 59). Products 370 and 372 exhibit potassium channel activating ability <2001FA841>. 

A series of /> ra-substituted ort o-nitroanilines 1274 is converted in this way to benzotriazolyl derivatives 1277, which are of interest as potassium channel activators. In the first step, nitroanilines 1274 are treated with salicylyl chloride to provide salicylamides 1275 in 70-95% yield. The nitro group is catalytically reduced, and the obtained intermediates 1276 are subjected to a reaction with nitrous acid, generated in situ from NaN02, to afford 5-substituted T(2-hydroxybenzoyl)-17/-benzotriazoles 1277 in 52-96% yield (Scheme 213) <2001FA827>. 

Several different changes in mitochondria occur during apoptosis. These include a change in membrane potential (usually depolarization), increased production of reactive oxygen species, potassium channel activation, calcium ion uptake, increased membrane permeability and release of cytochrome c and apoptosis inducing factor (AIF) [25]. Increased permeability of the mitochondrial membranes is a pivotal event in apoptosis and appears to result from the formation of pores in the membrane the proteins that form such permeability transition pores (PTP) may include a voltage-dependent anion channel (VDAC), the adenine nucleotide translocator, cyclophilin D, the peripheral benzodiazepine receptor, hexokinase and... 

Zeng, H., Lozinskaya, I.M., Lin, Z., Willette, R.N., Brooks, D.P. and Xu, X. (2006) Mallotoxin is a novel human ether-a-go-go-related gene (hERG) potassium channel activator. The Journal of Pharmacology and Experimental Therapeutics, 319, 957-962. 

Mitcheson, J.S., Chen, J. and Sanguinetti, M.C. (2000) Trapping of a methanesulfonanilide by closure of the hERG potassium channel activation gate. The Journal of General Physiology, 115, 229-240. 

There are now many examples of the industrial use of manganese(lll) salen catalyzed asymmetric epoxidations. For example, the as5mmetric epoxidation of a chromene derivative was central to the S5mthesis of the potassium channel activator BRL 55834 (Figure 11.5). ... 

Fig. 7.27 Structure of minoxidil a compound metabolized by sulphotransferases to a potassium channel activator.

Ion channel modulation represents another approach to positive inotropy [13]. Sodium channel modulators increase Na+ influx and prolong the plateau phase of the action potential sodium/calcium exchange then leads to an increase in the level of calcium available to the contractile elements, thus increasing the force of cardiac contraction [13,14]. Synthetic compounds such as DPI 201-106 and BDF 9148 (Figure 1) increase the mean open time of the sodium channel by inhibiting channel inactivation [15]. Importantly, BDF 9148 remains an effective positive inotropic compound even in severely failing human myocardium [16] and in rat models of cardiovascular disease [17]. Modulators of calcium and potassium channel activities also function as positive inotropes [13], but in the remainder of this article we shall focus on sodium channel modulators. 

Antihypertensive Agents. Hypertension (high blood pressure) is a significant risk factor for cardiovascular diseases such as angina heart attacks, and strokes. /(-Adrenoceptor (adrenergic nervous system receptors of the /(-type) antagonists (/(-blockers), calcium channel blockers, angiotensinconverting enzyme (ACE) inhibitors, and potassium channel activators... 

Heterocyclyloxy-2H-l-benzopyran potassium channel activators./. Med. Chem. 1990, 33, 2759-2767. 

The pharmacological treatment options for ACS include agents that either reduce oxygen demand (beta blockers) or increase oxygen supply (nitrates, potassium channel activators, calcium channel blockers) to the heart and antiplatelet (aspirin, ADP-receptor antagonists, GPIIb/llla receptor blockers) and antithrombin therapy (unfractionated heparin, low molecular weight heparin, direct thrombin inhibitors) (10). 

The potassium channel activator cromakalim is a mixture of trans-con-figured compounds. What relationship do these two stereoisomers have to each other ... 

Dost R, Rostock A, Rundfeldt (2004) The anti-hyperalgesic activity of retigabine is mediated by KCNQ potassium channel activation. Nauyn-Schmiedeberg s Arch Pharmacol 369 382-390... 

Wickenden AD, Krajewski JL, London B et al. (2008) ICA-27243 a novel, selective KCNQ2/Q3 potassium channel activator. Mol Pharmacol 73(3) 977-986... 

Mannhold R, Cruciani G, Weber H et al. (1999) 6-Substituted benzopyrans as potassium channel activators Synthesis, vasodilator properties, and multivariate analysis. J Med Chem 42 981-991... 

Additionally, a number of biologically significant molecules have in their structure a chiral nonracemic sulfinyl group. Among these molecules (Fig. 1), it is worth noting the new immunosuppressive thiaspirane sulfoxide Nuphar alkaloid type la and lb,13 the gastric antisecretory omeprazole 2,14 the new potassium channel activators of Rhone Poulenc aprikalim 3,15 the cyclic hexapeptide waiakeamide 4,16 the ACAT inhibitor 5,17 and the potent human immunodeficiency virus type 1 protease inhibitor 6.18... 

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