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Related Concept Videos

Direct-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship01:22

Direct-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship

Cholinergic agonists or cholinomimetics mimic the action of acetylcholine to stimulate the parasympathetic nervous system. They are categorized into direct-acting and indirect-acting agents. The direct-acting cholinergic drugs induce the parasympathetic response by directly binding to the muscarinic or nicotine receptors. In comparison, the indirect-acting cholinergic drugs prevent acetylcholine hydrolysis, indirectly contributing to the extended parasympathetic response.
The direct-acting...
Cholinergic Receptors: Muscarinic01:25

Cholinergic Receptors: Muscarinic

The pharmacological actions of acetylcholine are elicited via its binding to two families of cholinergic receptors or cholinoceptors, namely, muscarinic and nicotinic receptors. Muscarinic receptors are G protein-coupled receptors and have five subtypes, M1–M5. All mAChR subtypes are activated by acetylcholine and blocked by the antagonist, atropine. 
The subtypes M1, M3, and M5 couple with the Gq subunit and activate the phospholipase C (PLC) activity, mobilizing intracellular Ca2+. Activation...
Direct-Acting Cholinergic Agonists: Pharmacological Actions00:59

Direct-Acting Cholinergic Agonists: Pharmacological Actions

Direct-acting cholinergic agonists exert their pharmacological actions by mimicking the effects of acetylcholine on postsynaptic muscarinic receptors to generate parasympathetic responses. These agents elicit a range of physiological responses, including cardiovascular effects. For example, activation of muscarinic receptors induces bradycardia, decreased cardiac output, reduced peripheral resistance, and consequent hypotension. In the eye, stimulation of M3 receptors leads to smooth muscle...
Cholinergic Antagonists: Chemistry and Structure-Activity Relationship01:29

Cholinergic Antagonists: Chemistry and Structure-Activity Relationship

Cholinergic antagonists bind to cholinergic receptors and limit the effects of acetylcholine and other cholinergic agonists. Based on the specific cholinergic receptor affinity, these antagonists are classified as muscarinic or nicotinic. Anticholinergics interrupt parasympathetic innervations while sympathetic innervations remain uninterrupted. Muscarinic antagonists are also called 'muscarinic antagonists', 'antimuscarinics', or 'parasympatholytics'. Nicotinic antagonists are called...
Direct-Acting Cholinergic Agonists: Therapeutic Uses01:11

Direct-Acting Cholinergic Agonists: Therapeutic Uses

Direct-acting cholinergic agonists have many therapeutic uses in various medical fields. Choline esters, including acetylcholine, have limited clinical utility due to their non-selectivity and short duration of action. Still, acetylcholine and carbachol are applied topically during ophthalmologic surgery to induce miosis. Pilocarpine, a muscarinic and ganglionic stimulator, effectively treats open-angle glaucoma and alleviates xerostomia and dry mouth caused by radiotherapy or Sjögren syndrome.
Direct-Acting Cholinergic Agonists: Pharmacokinetics01:31

Direct-Acting Cholinergic Agonists: Pharmacokinetics

Direct-acting cholinergic agonists, such as synthetic choline esters and naturally occurring alkaloids, exert their effects by enhancing the actions of acetylcholine and stimulating the parasympathetic nervous system. Synthetic choline esters share structural similarities with acetylcholine. For example, they have a positively charged quaternary ammonium or onium group, contributing to their hydrophilic characteristics. As a result, they are poorly absorbed in the body through oral...

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Related Experiment Video

Updated: Jul 1, 2026

A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
07:41

A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators

Published on: February 20, 2018

Low Agonism and Balanced Pathway Modulation Distinguish an M1 Muscarinic Receptor Positive Allosteric Modulator

Huong T M Nguyen1,2, Elham Khajehali1, Vi Pham1

  • 1Drug Discovery Biology, Monash University, Parkville, Melbourne, Victoria 3052, Australia.

ACS Chemical Neuroscience
|June 30, 2026
PubMed
Summary

Positive allosteric modulators (PAMs) for M1 muscarinic acetylcholine receptors (mAChRs) show promise for cognitive disorders but cause side effects. This study reveals that low allosteric agonism and balanced efficacy modulation are key for safer M1 PAMs.

Keywords:
Alzheimer’s diseaseM1 muscarinic acetylcholine receptorsallosteric modulationbiased allosterismcognitionschizophreniasignaling pathways

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Quantifying Agonist Activity at G Protein-coupled Receptors
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Quantifying Agonist Activity at G Protein-coupled Receptors

Published on: December 26, 2011

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Last Updated: Jul 1, 2026

A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
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A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators

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Quantifying Agonist Activity at G Protein-coupled Receptors
11:45

Quantifying Agonist Activity at G Protein-coupled Receptors

Published on: December 26, 2011

Area of Science:

  • Neuroscience
  • Pharmacology
  • Molecular Biology

Background:

  • Positive allosteric modulators (PAMs) of the M1 muscarinic acetylcholine receptor (mAChR) are investigated for cognitive disorders like Alzheimer's disease.
  • Clinical translation is hindered by on-target cholinergic adverse effects, potentially linked to excessive allosteric agonism.

Purpose of the Study:

  • To comparatively analyze the pharmacology of five distinct M1 PAMs.
  • To elucidate the roles of allosteric cooperativity, efficacy modulation, and receptor regulation in M1 PAM-associated adverse effects.

Main Methods:

  • Utilized HEK293A cells expressing wild-type (hM1-WT) or phosphorylation-deficient (hM1-PD) human M1 mAChR.
  • Employed radioligand binding and functional assays to quantify binding affinity, cooperativity, allosteric agonism, and efficacy modulation.
  • Assessed G protein-dependent and β-arrestin-associated signaling pathways.

Main Results:

  • VU0486846, a PAM with low reported adverse effects, exhibited low allosteric agonism and weaker cooperativity but comparable efficacy modulation.
  • PAMs linked to adverse effects showed higher allosteric agonism, stronger cooperativity, and preferential β-arrestin signaling enhancement.
  • Phosphorylation site deficiency on M1 mAChR uncoupled allosteric agonism from efficacy modulation, highlighting phosphorylation's regulatory role.

Conclusions:

  • Low allosteric agonism and balanced efficacy modulation are crucial for improved M1 PAM tolerability.
  • Phosphorylation of M1 mAChR is a key regulator of allosteric signaling.
  • This research provides a framework for designing safer M1-targeted therapeutics by differentiating M1 PAM pharmacology beyond intrinsic agonism.