M3 receptors

DP Mamott, IG Dougall, P Meghani, Y-J Liu, DR Flower. Lead generation using pharmacophore mapping and three-dimensional database searching Application to muscarinic M3 receptor antagonists. J Med Chem 42 3210-3216, 1999. 

Silvetre, J. S., and Prous, J. (2005). Research on adverse drug events Muscarinic m3 receptor binding affinity could predict the risk of antipsycho tics to induce type 2 diabetes. Meth. Find. Exp. Clin. Pharmacol. 27 289-304. 

Anti-cholinergics Tiotropium bromide remains bound to M3-receptors for up to 36 h, and requires only daily intake, whereas other anti-cholinergics (e.g. ipratropium, oxytropium) have to be given up to four-times daily and are often used as maintenance treatment. Possible side-effects are dry mouth, metallic taste after inhalation and very rarely close-angle glaucoma. 

Muscarinic M3 Receptor. A pharmacophore model was derived from known M3 receptor antagonists, using the program DISCO, and 3D searching was performed by Unity 3D in the Astra Charnwood in-house compound repository and the databases of several commercial suppliers. The 172 compounds that fitted the pharmacophore were screened for their M3-antagonistic potency. Several compounds with micromolar and even submicromolar activities resulted, for example, compound 13 (A50 M3 antagonism 0.2pM pA2 = 6.67 Fig. 16.2) [85],... 

Ml and M3 receptors mediate the excitatory effects and since this postspike hyperpolarisation is blocked by phorbol esters and is therefore presumably dependent on IP3 production, one would expect it to be mediated through M] receptors (see above), especially as these are located postsynaptically. Unfortunately it does not appear to be affected by pirenzapine, the Mi antagonist. By contrast, muscarinic inhibition of the M current is reduced by the Mi antagonist but as it is not affected by phorbol esters is not likely to be linked to IP3 production, an Mi effect. 

Pilocarpine directly stimulates the muscarinic (M3) receptors of the ciliary body which causes contraction of the ciliary muscle. This results in widening of the spaces in the trabecular meshwork, which causes an increase in aqueous humor outflow and reduces IOP by 20% to 30%. 

Ecothiophate iodide and denecarium bromide inhibit acetylcholinesterase. Inhibition of this enzyme increases the availability of acetylcholine at the nerve junction, thus increasing the stimulation of the muscarinic (M3) receptors of the ciliary... 

Furthermore, these allosteric effects were shown to be truly subtype specific, depending on the nature of the allosteric modulating compound. Thus, alcuronium exerts positive copperativity with [3H]NMS at the M2 and M4 but not at the Mi and M3 receptors [26,27], while other neuromuscular junction blockers such as stercuronium, pancuronium, and d-tubocurarine have been shown to exhibit their effects via an allosteric mechanism specifically on the M2 receptors [28-30]. 

Muscarinic and dopaminergic pathways in the CNS interact in control of numerous pathways implicated in diseases, especially those controlling involuntary motor systems. Muscarinic effects on dopamine release are mediated in several ways via different mAChR subtypes. Thus mAChR facilitation of DA release appears to involve M4 receptors on GABA projection neurons to the striatum, while M3 receptors on striatal DA neurons are predicted to inhibit striatal DA release [12],... 

Acetylcholine is the neurotransmitter that mediates both volitional and involuntary contractions of the bladder. Bladder smooth muscle cholinergic receptors are mainly of the M2 variety however, M3 receptors are responsible for both emptying contraction of normal micturition and involuntary bladder contractions, which can result in UI. Therefore, most pharmacologic antimuscarinic therapy is anti-M3 based. 

Sawyer, G. W. and Ehlert, F. J. (1999) Muscarinic M3 receptor inactivation reveals a pertussis toxin-sensitive contractile response in the guinea pig colon evidence for M2/M3 receptor interactions../. Pharmacol. Exp. Ther. 289,464-476. 

Muscarinic M3 receptor Antagonist Acute (gastrointestinal system) Reduced GI motility Darifenacin26... 

Yamamoto T, Yamashita N, Kuwabara M, et al. (2002) Mutation screening of the muscarinic m2 and m3 receptor genes in asthmatics, outgrow subjects, and normal controls. Ann Genet. 45, 109-113. 

Kato M, Komamura K, Kitakaze M. (2006) Tiotropium, a novel muscarinic M3 receptor antagonist, improved symptoms of chronic obstructive pulmonary disease complicated by chronic heart failure. Circ J 70 1658-1660. 

Ester functions present in molecules tend to be considered labile although steric effects etc. may be utilized to produce drugs without inherent chemical or metabolic problems due to ester lability. For instance a series of antimuscarinic compounds which had selectivity for the M3 receptor (Figure 7.18) were stabilized by the incorporation of a hydroxy ethyl side chain or a cyclic ring system at positions surrounding the ester function. Presumably the proximity of these groups to the ester function (carbonyl) prevents close approach of the attacking nucleophile, in this case probably a serine hydroxyl. 

Muscarinic M2 receptor CHRM2 Agonism Vagal effects (key role in the control of heart rate and smooth muscle activity) Bradycardia. Antagonism May induce cardiac side effects (palpitations, dysrhythmia) or peripheral edema, bronchoconstriction can result from presynaptic M2 receptor antagonism if postsynaptic M3 receptors are not also blocked. 

I. Hellgren, A. Mustafa, M. Riazi, I. Suliman, C. Sylven, A. Adem, Muscarinic M3 receptor subtype gene expression in the human heart. Cell Mol. Life Sci. 57 (2000) 175-180. 

Selective muscarinic receptor blocker. It inhibits gastric secretion. Thus is effective in peptic ulcer patients and promotes ulcer healing. It does not produce atropinic side effect (due to blockade of and M3 receptors). 

Neural vagal stimulation reieases acetylcholine, which acts on muscarinic M3 receptors, leading to increased cytosoiic Ca2+. 

In the intact organism, intravascular injection of muscarinic agonists produces marked vasodilation. However, earlier studies of isolated blood vessels often showed a contractile response to these agents. It is now known that acetylcholine-induced vasodilation arises from activation of M3 receptors and requires the presence of intact endothelium (Figure 7-5). 

Autonomic nerves can regulate coronary arteriolar tone. Acetylcholine released from postganglionic parasympathetic nerves relaxes coronary arteriolar smooth muscle via the NO/cGMP pathway in humans as described above. Damage to the endothelium, as occurs with atherosclerosis, eliminates this action, and acetylcholine is able to contract arterial smooth muscle and produce vasoconstriction. Skeletal muscle receives sympathetic cholinergic vasodilator nerves, but the view that acetylcholine caused vasodilation in this vascular bed has not been verified experimentally. Moreover, NO, rather than acetylcholine, may be released from neurons. However, this vascular bed responds to exogenous choline esters because of the presence of M3 receptors on endothelial and smooth muscle cells. 

Muscarinic agonists stimulate the detrusor muscle and relax the trigone and sphincter muscles of the bladder, thus promoting voiding. The function of M2 and M3 receptors in the urinary bladder appears to be the same as in intestinal... 

All five muscarinic receptor subtypes have been detected in the central nervous system. The roles of Mx through M3 have been analyzed by means of experiments in knockout mice. The Mx subtype is richly expressed in brain areas involved in cognition. Knockout of Mx receptors was associated with impaired neuronal plasticity in the forebrain, and pilocarpine did not induce seizures in Mx mutant mice. The central nervous system effects of the synthetic muscarinic agonist oxotremorine (tremor, hypothermia, and antinociception) were lacking in mice with homozygously mutated M2 receptors. Animals lacking M3 receptors, especially those in the hypothalamus, had reduced appetite and diminished body fat mass. 

Bethanechol Muscarinic agonist t negligible effect at nicotinic receptors Activates Mi through M3 receptors in all peripheral tissues causes increased secretion, smooth muscle contraction (except vascular smooth muscle relaxes), and changes in heart rate Postoperative and neurogenic ileus and urinary retention Oral and parenteral, duration 30 min does not enter central nervous system (CNS) Toxicity Excessive parasympathomimetic effects, especially bronchospasm in asthmatics Interactions Additive with other parasympathomimetics... 

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