Potassium channel opening drugs

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

Beta blockers, calcium channel blockers and potassium channel openers detailed pharmacology is given in chapter Antihypertensive drugs. ... 

Another practically important class of drugs that also interact with the sulfonylurea receptor are potassium channel openers. In keeping with our expectations, they will reduce membrane excitability. These are mostly targeted at the Kjj. channels in the vascular smooth muscle cells (Figure 5.13). 

In addition to the widely reported techniques of amide bond formation, transesterification, and hydrolysis, enzymic enantioselective oxidation is also used in the synthesis of single isomer drugs. Patel described the elficient oxidation of benzopyran (75), an intermediate in thesynthesisof potassium channel openers (123). The transformationwas ef-fected w i t h a cell suspension of MortiereUa raman-niana with glucose over a 48-h period, the isolated product (77) was obtained in a 76%yield with an optical purity of 97%and a chemical purity of 98%, as shown in Pig. 18.32. 

The potassium-channel openers are thought to work by opening a subset of K -channels, which leads to membrane stabilization. Agents such as this have so far been proposed as vasodilators for the treatment of hypertension or heart failure, e.g. nicorandil. They may, however, become used for their smooth muscle relaxant action at other sites, e.g. in the aihvays as ANTIASTHMATIC AGENTS, or for bladder hyperexcitability. Other examples of drugs that work at least partly by this mechanism are cromakalim, diazoxide, pinacidil and minoxidil. See POTASSIUM-CHANNEL ACTIVATORS. 

Hydroxylation of sodium and potassium enolates side reaction with lithium Substrate controlled stereoselectivity asymmetric hydroxylation Asymmetric hydroxylation with camphor sultam derivatives Asymmetric synthesis of tetracycline precursors Synthesis of a calcium channel opening drug Asymmetric synthesis ofbuproprion Summary... 

Certain synthetic potassium channel openers have been shown to activate K a channels, such as NS-004 (Sargenteta/., 1993)andNS-1619. However, iberiotoxin was unable to reverse the functional effects of NS-004, and therefore its mechanism of action may also involve inhibition of calcium current rather than activation of K a channels. Some drugs (e.g., cro-makalim) that activate K -p channels have also been shown to activate K channels in aortic smooth muscle cells but not in other types of arterial smooth muscle. Since blockers of K a channels (charybdotoxin and <1 mM TEA+) had no effect on membrane potential hyperpolarizations or dilations to any of... 

Although several potassium channel openers have been used in research for many years, only one, minoxidil. Is approved for use In humans for treating hypertension. Minoxidil is the N-oxide of a piperidinopyrimidine hypotensive agent, with a pKa of 4.6, and is not an active hypotensive drug until It Is metabolized by hepatic sulfotransferase to minoxidil N-O-sulfate (9). 

Being effective arterial dilators, potassium-channel openers are used in the treatment of hypertension. These drugs are not first-line therapy for hypertension because of their side effects therefore, they are relegated to treating refractory, severe hypertension. They generally are used in conjunction with a p-blocker and a diuretic to attenuate the reflex tachycardia and retention of sodium and fluid, respectively. 

Duty S, Weston AH. Potassium channel openers. Pharmacological effects and future uses. Drugs 1990 40 785-791. 

Minoxidil (6-amino-l,2-dihydro-l-hydroxy-imino-4-piperidino pyrimidine) has been shown to regrow hair with minimal side effects. This drug is a vasodilator and a potassium channel opener. It was originally developed... 

Figure 3.18 (a) The N-cyanoguanidine drug cimetadine. (b) A potent potassium channel opener... 

Several classes of drugs, notably the antipsychotics, discussed in Chapter 34, interfere with dopaminergic transmission. In general, dopamine appears to be an inhibitory neurotransmitter. Five dopamine receptors have been identified the most important and best studied are the Dj. and D2.receptor groups. The Dj receptor, which increases cyclic adenosine monophosphate (cAMP) by activation of adenylyl cyclase, is located primarily in the region of the putamen, nucleus accum-bens, and in the olfactory tubercle. The D2 receptor decreases cAMP, blocks certain calcium channels, and opens certain potassium channels. 

Lamotrigine is an anticonvulsant drug that attenuates some forms of cortical glutamate release via inhibition of sodium, calcium, and potassium channels. An open-label case series (Uvebrant and Bauziene, 1994) and a case report (Davanzo and King, 1996) described improvement in autistic symptoms and self-injurious behavior, irritability, disturbed sleep, and social impairment in autistic children and an 18-year-old female with profound mental retardation, respectively, who were treated for epilepsy. 

---