Potassium channels agents

There ate many classes of anticonvulsant agent in use, many associated with side effect HabiUties of unknown etiology. Despite many years of clinical use, the mechanism of action of many anticonvulsant dmgs, with the exception of the BZs, remains unclear and may reflect multiple effects on different systems, the summation of which results in the anticonvulsant activity. The pharmacophore stmctures involved are diverse and as of this writing there is htde evidence for a common mechanism of action. Some consensus is evolving, however, in regard to effects on sodium and potassium channels (16) to reduce CNS excitation owing to convulsive episodes. 

An alternative approach to stimulate cholinergic function is to enhance the release of acetylcholine (ACh). Compounds such as the aminopyridines increase the release of neurotransmitters (148). The mechanism by which these compounds modulate the release of acetylcholine is likely the blockade of potassium channels. However, these agents increase both basal (release in the absence of a stimulus) and stimulus-evoked release (148). 4-Aminopyridine [504-24-5] was evaluated in a pilot study for its effects in AD and found to be mildly effective (149). 

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. 

Katp channels are the targets for two classes of therapeutic agents, hypoglycaemic drugs like glibencla-mide or nateglinide and potassium channel openers like... 

Paul, A.A., Witchel, H.J. and Hancox, J. C. (2001) Inhibition of HERG potassium channel current by the class la antiarrhythmic agent disopyramide. Biochemical and Biophysical Research Communications, 280, 1243—1250. 

The obvious exceptions to the general requirements for Class III activity described above are (68) and (70). These two compounds appear to be selective Class III agents however, they lack an appropriate Q moiety. It is interesting to speculate whether these compounds bind to an alternate domain in the potassium channel or, possibly for (68), an entirely different site (for example, sodium or calcium channels) to effect their Class III activity. 

Repaglinide en nateglinide are not sulfonylurea agents but their mechanism of action is very alike. Repaglinide is the first carbamoylmethyl-benzoic acid derivative that has been registred for the treatment of diabetes mellitus. It closes ATP-dependent potassium channels in the beta cell membrane with consequent depolarization, opening of calcium channels and increased insulin release. It is rapidly absorbed with peak plasma levels after 1 hour. It has a protein binding of over 98%. 

The potassium channel, on the other hand, is blocked by both tetraethylammonium salts (7.3, TEA) and nonyl-triethylammonium (7.4) salts, indicating the presence of a hydrophobic binding site that accommodates the nonyl group. Both blocking agents must be applied intra-axonally, which is understandable if one considers that the K current is always directed outward. 

Nicorandil and several other investigational antianginal agents appear to combine the activity of nitric oxide release with potassium channel-opening action, thus providing an additional mechanism for causing vasodilation. 

Several first-generation Hi antagonists are potent local anesthetics. They block sodium channels in excitable membranes in the same fashion as procaine and lidocaine. Diphenhydramine and promethazine are actually more potent than procaine as local anesthetics. They are occasionally used to produce local anesthesia in patients allergic to conventional local anesthetic drugs. A small number of these agents also block potassium channels this action is discussed below (see Toxicity). 

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... 

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