The pharmacology of McN-A-343

Mitchelson, F.

doi:10.1016/j.pharmthera.2012.05.008

Cited by 17 publications

(21 citation statements)

References 286 publications

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“…2a). In contrast, McN-A-343, a M 1 - and M 4 -selective bitopic orthosteric/allosteric partial agonist (Mitchelson, 2012; Valant et al, 2008), up to 64 μM triggered negligible DMR, identical to the negative control (buffer), in the six cell lines (Fig. 2b), suggesting that there is no or little DMR response originating from endogenous M 1 or M 4 receptors in all the six cell lines.…”

Section: Resultsmentioning

confidence: 97%

Label-free cell phenotypic assessment of the biased agonism and efficacy of agonists at the endogenous muscarinic M3 receptors

Deng

Sun

2013

Journal of Pharmacological and Toxicological Methods

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Introduction Efficacy describes the property of a ligand that enables the receptor to change its behavior towards the host cell, while biased agonism defines the ability of a ligand to differentially activate some of the vectorial pathways over others mediated through the receptor. However, little is known about the molecular basis defining the efficacy of ligands at G protein-coupled receptors. Here we characterize the biased agonism and cell phenotypic efficacy of seven agonists at the endogenous muscarinic M3 receptors in six different cell lines including HT-29, PC-3, HeLa, SF268, CCRF-CEM and HCT-15 cells. Methods Quantitative real-time PCR and multiple label-free whole cell dynamic mass redistribution (DMR) assays were used to determine the functional muscarinic receptors in each cell line. DMR pathway deconvolution assay was used to determine the pathway biased activity of the muscarinic agonists. Operational agonism model was used to quantify the pathway bias, while macro-kinetic data reported in literature was used to analyze the biochemical mechanism of action of these agonists. Results Quantitative real-time PCR and ligand pharmacology studies showed that all the native cell lines endogenously express functional M3 receptors. Furthermore, different agonists triggered distinct DMR signals in a specific cell line as well as in different cell lines. DMR pathway deconvolution using known G protein modulators revealed that the M3 receptor in all the six cell lines signals through multiple G protein-mediated pathways, and certain agonists display biased agonism in a cell line-dependent manner. The whole cell efficacy and potency of these agonists were found to be sensitive to the assay time as well as the cell background. Correlation analysis suggested that the whole cell efficacy of agonists is correlated well with their macro-dissociation rate constants. Discussion This study implicates that the endogenous M3 receptors are coupled to multiple pathways, and the muscarinic agonists can display distinct biased agonism and whole cell phenotypic efficacy.

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Section: Resultsmentioning

confidence: 97%

Label-free cell phenotypic assessment of the biased agonism and efficacy of agonists at the endogenous muscarinic M3 receptors

Deng

Sun

2013

Journal of Pharmacological and Toxicological Methods

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“…Several compounds that once were considered to be monovalent have since been suspected to be bitopic. A great deal of work by multiple labs has recently demonstrated that most reported allosteric agonists, e.g., those for M 1 , are actually bitopic ligands (93, 96-98). These ligands bind to a distinct allosteric site that engenders functional M 1 selective activation, but at higher concentrations, the ligands also bind at the orthosteric site and typically act as orthosteric antagonists of M 2-5 ; moreover, there are molecular switches that abolish binding at the allosteric site, leading to ligands that are pan -orthosteric mAChR antagonists.…”

Section: The Emerging Complexity Of Designing Allosteric Ligands For mentioning

confidence: 99%

Drugs for Allosteric Sites on Receptors

Wenthur

Gentry

Mathews

et al. 2014

Annu. Rev. Pharmacol. Toxicol.

219

272

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The presence of druggable, topographically distinct allosteric sites on a wide range of receptor families has offered new paradigms for small molecules to modulate receptor function. Moreover, ligands that target allosteric sites offer significant advantages over the corresponding orthosteric ligands in terms of selectivity, including subtype selectivity within receptor families, and can also impart improved physicochemical properties. However, allosteric ligands are not a panacea. Many chemical issues (e.g., flat structure-activity relationships) and pharmacological issues (e.g., ligand-biased signaling) that are allosteric centric have emerged. Notably, the fact that allosteric sites are less evolutionarily conserved leads to improved selectivity; however, this can also lead to species differences that can hinder safety assessment. Many allosteric ligands possess molecular switches, wherein a small structural change (chemical or metabolic) can modulate the mode of pharmacology or receptor subtype selectivity. As the field has matured, as described here, key principles and strategies have emerged for the design of ligands/drugs for allosteric sites.

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“…McN-A-343 is a selective M1 muscarinic agonist that stimulates muscarinic transmission in sympathetic ganglia. This explains the tachycardic effect of the drug [26].…”

Section: Discussionmentioning

confidence: 91%

“…McN-A-343 is a partial agonist with similar affinity at all five muscarinic acetylcholine receptor subtypes and its relative selectivity depends on a higher efficacy at the M1 (and M4) subtypes [26]. Being a partial agonist, its action is also dependent on other factors, such as receptor density and coupling efficacy between receptor activation and tissue response [26]. In addition, McN-A-343 is a bitopic agonist, because it binds to an allosteric site on the M2 receptor as well as to the orthosteric site [27].…”

Section: Discussionmentioning

confidence: 99%

A Decreased Expression and Functionality of Muscarinic Cholinergic Receptor in Acute Chagas Myocarditis

Labrador-Hernández¹,

Jimenez²,

León³

et al. 2014

WJCD

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Background: Chagas disease is still a public health problem because of the remaining high prevalence, the expansion of the disease into developed countries and the re-emergences by oral transmission outbreaks. Chagas cardiomyopathy evolves as a consequence of an autonomic unbalance where the parasympathetic tone is undermined. Objective: To determine the functionality and expression of muscarinic cholinergic receptors in acute Chagas disease. Methodology: 62 male, 3-week-old Sprague Dawley rats were assayed; 32 were infected with Trypanosoma cruzi trypomastigotes and 30 were healthy controls. Electrocardiographic studies were conducted in the absence or presence of direct muscarinic (oxotremorine and McN-A-343) or indirect agonists (phenylephrine) or antagonist (pirenzepine). Muscarinic M1 and M2 receptor expression was determined by radioligand [ 3 H]-QNB binding assay and immunoblot. Results: Chagasic acute myocarditis was sustained by electrocardiographic signs and histopathological findings. Bradycardia induced by oxotremorine was significantly higher in healthy rats (HR) and the differences were enhanced by CsCl. In the absence of the agonist, CsCl induced a greater bradycardia in chagasic rats (ChR). In HR McN-A-343 induced tachycardia, however it induces bradycardia in the presence of a acetylcholinesterase inhibitor (neostigmine); no effects were observed in ChR. Pirenzepine induced a higher tachycardia in HR. Phenylephrine in the presence of pirenzepine induced a similar bradycardia in both groups, but recovery was faster in ChR. Muscarinic M1 and M2 receptor density was higher in HR. Conclusion: Muscarinic receptor expression and functionality are decreased * Corresponding author. M. Labrador-Hernández et al. 306in the acute Chagas disease that could impact the evolution and prognosis of the disease.

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The pharmacology of McN-A-343

Cited by 17 publications

References 286 publications

Label-free cell phenotypic assessment of the biased agonism and efficacy of agonists at the endogenous muscarinic M3 receptors

Label-free cell phenotypic assessment of the biased agonism and efficacy of agonists at the endogenous muscarinic M3 receptors

Drugs for Allosteric Sites on Receptors

A Decreased Expression and Functionality of Muscarinic Cholinergic Receptor in Acute Chagas Myocarditis

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