Muscarinic receptors mechanisms

Miller AD, Blaha CD. 2005. Midbrain muscarinic receptor mechanisms underlying regulation of mesoaccumbens... 

Thus, the high potency and functional M selectivity of (S)-4-F-MePyMcN make this compound suitable for the study of muscarinic receptor mechanisms. Due to its Mj-agonistic and M2-antagonistic properties (S)-4-F-MePyMcN may be considered as an important tool for future drug research in the field of cognitive disorders. Its partial agonistic nature may be ad-... 

Florio, V. A., and Stemweis, P. C. (1989). Mechanism of muscarinic receptor action on G0 in reconstituted phospholipid vesicles. J. Biol. Chem. 264 3909-3915. 

Traumatic brain injury is the most common cause of death in subjects under the age of 40, and an important risk factor for AD. Loss of hippocampal cells and depletion of ACh and of muscarinic receptors can be attenuated in injured experimental animals, improve blood perfusion in ischemic areas and increase cholinergic transmission in cortex and hippocampus the same mechanism invoked for treatment of VD. 

Jooste E, Klafter F, Hirshman CA, Emala CW A 31 mechanism for rapacuronium-induced bronchos-pasm M2 muscarinic receptor antagonism Anesthesiology 2003 98 906. 

The adverse side-effects of the TCAs, coupled with their toxicity in overdose, provoked a search for compounds which retained their monoamine uptake blocking activity but which lacked the side-effects arising from interactions with Hj, aj-adreno-ceptors and muscarinic receptors. One of the first compounds to emerge from this effort was iprindole, which has an indole nucleus (Fig. 20.3). This turned out to be an interesting compound because it has no apparent effects on monoamine uptake and is not a MAO inhibitor. This, together with its relatively minor antimuscarinic effects, led to it commonly being described as an atypical antidepressant. Mechanisms that could underlie its therapeutic actions have still not been identified but, in any case, this drug has now been withdrawn in the UK. 

Many measurements in pharmacology rely on a chain of events following receptor activation to produce a measurable response — for example, contraction of the smooth muscle of a piece of guinea-pig ileum in response to muscarinic receptor activation by acetylcholine. This means that the relationship between receptor occupancy and response is likely to be complex, and mechanisms of drug action in such systems are often difficult to define. 

EEG slow waves. The differential EEG and ACh responses to dialysis delivery of AF-DX 116 (M2/M4) versus pirenzepine (M1/M4) supports the conclusion that, in B6 mouse, postsynaptic muscarinic receptors of the Ml subtype form one receptor mechanism by which ACh activates the EEG (Douglas et al, 2002a). The data summarized in Fig. 5.11 provide direct measures of G protein activation in basal forebrain and prefrontal cortex by muscarinic cholinergic receptors (DeMarco et al, 2004). The in vitro data of Fig. 5.11A indicate the presence of functional muscarinic receptors in regions of B6 mouse prefrontal cortex where in vivo microdialysis studies (Douglas et al, 2002a, b) revealed modulation of ACh release and EEG by pre- and postsynaptic muscarinic receptors (Figs. 5.9 and 5.10). 

Fig. 11.4. Model for cholinergic signalling in the intestinal mucosa, providing a possible rationale for AChE secretion by parasitic nematodes. ACh released from enteric cholinergic motor neurons stimulates chloride secretion, mucus secretion and Paneth cell exocytosis through muscarinic receptors. Secretory responses may be modulated by mast cell mediators, either directly or via the induction of neural reflex programmes. The role of muscarinic receptor-positive cells in the lamina propria of rats infected with N. brasiliensis is undetermined, as are potential mechanisms of trans-epithelial transport of the enzymes. Adapted from Cooke (1984).

Membrane depolarization typically results from an increase in Na+ conductance. In addition, mobilization of intracellular Ca2+ from the endoplasmic or sarcoplasmic reticulum and the influx of extracellular Ca2+ appear to be elicited by ACh acting on muscarinic receptors (see Ch. 22). The resulting increase in intracellular free Ca2+ is involved in activation of contractile, metabolic and secretory events. Stimulation of muscarinic receptors has been linked to changes in cyclic nucleotide concentrations. Reductions in cAMP concentrations and increases in cGMP concentrations are typical responses (see Ch. 21). These cyclic nucleotides may facilitate contraction or relaxation, depending on the particular tissue. Inhibitory responses also are associated with membrane hyperpolarization, and this is a consequence of an increased K+ conductance. Increases in K+ conductance may be mediated by a direct receptor linkage to a K+ channel or by increases in intracellular Ca2+, which in turn activate K+ channels. Mechanisms by which muscarinic receptors couple to multiple cellular responses are considered later. 

Schwab BW, Costa LG, Murphy SD. 1983. Muscarinic receptor alterations as a mechanism ot anticholinesterase (EC 3.1.1.7) tolerance. Toxicol Appl Pharmacol 71 14-23. 

The first step in treatment of anticholinesterase poisoning should be injection of increasing doses of atropine sulfate to block all adverse effects resulting from stimulation of muscarinic receptors. Since atropine will not alleviate skeletal and respiratory muscle paralysis, mechanical respiratory support may be required. 

Dicyclomine (Bentyl), oxybutynin (Ditropan), and tolterodine (Detrol) are nonselective smooth muscle re-laxants that produce relatively little antagonism of muscarinic receptors at therapeutic concentrations. The mechanism of relaxation is not known. Finally, some other classes of drugs can act in part as muscarinic antagonists. For example, the antipsychotics and antidepressants produce antimuscarinic side effects (e.g., dry mouth). 

Mechanism of Action An acetylcholine antagonist that inhibits the action of acetylcholine by competing with acetylcholine for common binding sites on muscarinic receptors, which are located on exocrine glands, cardiac and smooth-muscle ganglia, and intramural neurons. This action blocks all muscarinic effects. Therapeutic Effect Decreases GI motility and secretory activity, and GU muscle tone (ureter, bladder) produces ophthalmiccycloplegia, and mydriasis. 

Mechanism of Action Anticholinergic alkaloids that inhibit the action of acetylcholine at postganglionic (muscarinic) receptor sites. Morphine (10% of opium) depresses cerebral cortex, hypothalamus, and medullary centers. Therapeutic Effect Decreases digestive secretions, increases GI muscle tone, reduces G1 force, alters pain perception and emotional response to pain. 

Mechanism of Action A urinary antispasmodic agent that acts as a direct antagonist at muscarinic receptor sites in cholinergically innervated organs. Blockade of the receptors limits bladder contractions. Therapeutic Effect Reduces symptoms of bladder irritability and overactivity improves bladder capacity. 

Mechanism of Action A peripheral anticholinergic agent that has limited ability to cross the blood-brain barrier and provides a peripheral blockade of muscarinic receptors. Therapeutic Effect Reduces the volume and the total acid content of gastric secretions, inhibits salivation, and reduces gastrointestinal motility. 

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