Potassium muscarinic receptors

The anainoacridines, tacrine (19) and its 1-hydroxy metaboUte, velnacrine (20), are reversible inhibitors of AChE. Tacrine was synthesi2ed in the 1940s and has been used clinically for the treatment of myasthenia gravis and tardive dyskinesia (115). Placebo-controUed studies have indicated modest efficacy of tacrine to treat AD dementia (122,123) and in 1993 the dmg was recommended for approval by the PDA under the trade name Cognex. Tacrine (19) has been shown to interact with sites other than AChE, such as potassium channels (124) and muscarinic receptors. However, these interactions are comparatively weak and are not thought to contribute to the biological activity of the dmg at therapeutic levels (115). 

Parasympathetic stimulation causes a decrease in heart rate. Acetylcholine, which stimulates muscarinic receptors, increases the permeability to potassium. Enhanced K+ ion efflux has a twofold effect. First, the cells become hyperpolarized and therefore the membrane potential is farther away from threshold. Second, the rate of pacemaker depolarization is decreased because the outward movement of K+ ions opposes the effect of the inward movement of Na+ and Ca++ ions. The result of these two effects of potassium efflux is that it takes longer for the SA node to reach threshold and generate an action potential. If the heart beat is generated more slowly, then fewer beats per minute are elicited. 

Muscarinic receptor activation causes inhibition of adenylyl cyclase, stimulation of phospholipase C and regulation of ion channels. Many types of neuron and effector cell respond to muscarinic receptor stimulation. Despite the diversity of responses that ensue, the initial event that follows ligand binding to the muscarinic receptor is, in all cases, the interaction of the receptor with a G protein. Depending on the nature of the G protein and the available effectors, the receptor-G-protein interaction can initiate any of several early biochemical events. Common responses elicited by muscarinic receptor occupation are inhibition of adenylyl cyclase, stimulation of phos-phoinositide hydrolysis and regulation of potassium or other ion channels [47] (Fig. 11-10). The particular receptor subtypes eliciting those responses are discussed below. (See also Chs 20 and 21.)... 

Sir Henry Dale noticed that the different esters of choline elicited responses in isolated organ preparations which were similar to those seen following the application of either of the natural substances muscarine (from poisonous toadstools) or nicotine. This led Dale to conclude that, in the appropriate organs, acetylcholine could act on either muscarinic or nicotinic receptors. Later it was found that the effects of muscarine and nicotine could be blocked by atropine and tubocurarine, respectively. Further studies showed that these receptors differed not only in their molecular structure but also in the ways in which they brought about their physiological responses once the receptor has been stimulated by an agonist. Thus nicotinic receptors were found to be linked directly to an ion channel and their activation always caused a rapid increase in cellular permeability to sodium and potassium ions. Conversely, the responses to muscarinic receptor stimulation were slower and involved the activation of a second messenger system which was linked to the receptor by G-proteins. 

Trautwein W, Osterrieder W, and Noma A (1980) Potassium channels and the muscarinic receptor in the sino-atrial node of the heart in Drug Receptors and their Effectors, ed. N.J.M. Birdsall (New York Macmillan) pp 5-22... 

More recently it has become clear that also the function of G proteins can be altered. There are a small number of proteins that have been found to associate with G proteins and to affect their function. These proteins include the growth cone associated protein GAP-43, which has been found to enhance GTP binding by Gq in a manner similar to receptors [26], and a complex between the small GTP-binding protein ras p21 and its GTPase activating protein (ras-GAP) which impair coupling of muscarinic receptors to potassium channels [27]. 

Acetylcholine Approximately 5% of brain neurons have receptors for ACh. Most CNS responses to ACh are mediated by a large family of G protein-coupled muscarinic M receptors that lead to slow excitation when activated. The ionic mechanism of slow excitation involves a decrease in membrane permeability to potassium. Of the nicotinic receptors present in the CNS (they are less common than muscarinic receptors), those on the Renshaw cells activated by motor axon collaterals in the spinal cord are the best-characterized. Drugs affecting the activity of cholinergic systems in the brain include the acetylcholinesterase inhibitors used in Alzheimer s disease (eg, tacrine) and the muscarinic blocking agents used in parkinsonism (eg, benztropine). 

The Pinner reaction of glycolonitrile (68) with the propylenediamine (69) followed by treatment with thionyl chloride gave the chloromethylpyrimid-ine (70). Horenstein-Pahlicke esterification of the glycolic acid (71) with (70) in the presence of potassium iodide gave oxyphencyclimine (72) Scheme 5.17.) [73, 74] which possesses anticholinergic effects. The R(+) enantiomer has 29 times the potency of the S(-) form as a muscarinic receptor inhibitor [75]. 

A number of bench-scale processes with Ru/P P/N N catalysts are summarized in Fig. 13. Dow/Chirotech [91] used Ru/Xyl-PhanePhos/dpen for the hydrogenation of p-fluoro acetophenone. Kanto Chemicals developed a very effective Ru/bdpp/N N catalyst (the only case where the diphosphine is not a biaryl type) and applied it to the large scale hydrogenation of acetophenone [92] and of a quinuclidine [93] for a muscarinic receptor antagonist. Nycomed/JMC [94] scaled up the hydrogenation of rather complex ketone intermediate for the synthesis of a potassium competitive acid blocker. 

Figure 1 Model of cat carotid body s components thought to he involved in carotid body chemotransduction. NTS nucleus tractus solitarii in the hrainstem PG petrosal ganglion Al, A2a adenosine receptors P2X2 purinoceptor Ml, M2 types of muscarinic receptors N nicotinic receptors Dl, D2 dopamine receptors K potassium channels VGCC voltagegated calcium channels Ach acetylcholine DA dopamine NE norepinephrine SP substance P ATP adenosine triphosphate NO nitric oxide. The glomus cell, embraced by the calyx type sensory afferent fiber, contains several putative neurotransmitters. It is highly unlikely that every glomus cell contains all the listed neurotransmitters. Presumably the neurotransmitter can act wherever the appropriate receptors are located, postsynaptically as well as presynaptically. See text for postulated steps in the release of the neurotransmitters.

It is an agonist of peripheral and central ACh receptors, with a 100-fold selectivity for nicotinic receptors over muscarinic receptors (Aronstam and Witkop, 1981). It binds to tiie ACh receptor at the same position as ACh, causing sodium/potassium ion channels to open and inducing a depolarizing blockade. Anatoxin-a is more... 

SA node and A-V fibers become dominant. Activation of M2 receptors increases the potassium permeability and reduces cAMP levels, slowing the rate of depolarization and decreasing the excitability of SA node and A-V fiber cells. This results in marked bradycardia and a slowing of A-V conduction that can override the stimulation of the heart by catecholamines released during sympathetic stimulation. In fact, very high doses of a muscarinic agonist can produce lethal bradycardia and A-V block. Choline esters have relatively minor direct effects on ventricular function, but they can produce negative inotropy of the atria. 

The direct cardiac actions of muscarinic stimulants include the following (1) an increase in a potassium current (Ik(acii)) in atrial muscle cells and in the cells of the sinoatrial and atrioventricular nodes as well (2) a decrease in the slow inward calcium current (Ica) in heart cells and (3) a reduction in the hyperpolarization-activated current (If) that underlies diastolic depolarization. All of these actions are mediated by M2 receptors and contribute to slowing the pacemaker rate. Effects (1) and (2) cause hyperpolarization and decrease the contractility of atrial cells. 

Terfenadine binds to peripheral H-1 receptors. Receptor affinity for muscarinic, a, and /i-adrenergic receptors is low. Poor penetration of terfenadine across the blood-brain barrier limits central nervous system effects. Therefore, terfenadine is classified as nonsedating and lacks anticholinergic side effects. However, accumulation of the parent drug, terfenadine, results in prolongation of the QT interval by blocking the delayed rectifier potassium current in the heart. Prolongation of the QT interval can lead to torsade de pointes and death. 

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