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Cholinergic Receptors: Muscarinic

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.
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Allosteric Regulation

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Allosteric regulation of enzymes occurs when the binding of an effector molecule to a site that is different from the active site causes a change in the enzymatic activity. This alternate site is called an allosteric site, and an enzyme can contain more than one of these sites. Allosteric regulation can either be positive or negative, resulting in an increase or decrease in enzyme activity. Most enzymes that display allosteric regulation are metabolic enzymes involved in the degradation or...

Allosteric Regulation

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Allosteric regulation of enzymes occurs when the binding of an effector molecule to a site that is different from the active site causes a change in the enzymatic activity. This alternate site is called an allosteric site, and an enzyme can contain more than one of these sites. Allosteric regulation can either be positive or negative, resulting in an increase or decrease in enzyme activity. Most enzymes that display allosteric regulation are metabolic enzymes involved in the degradation or...

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Cholinergic Antagonists: Chemistry and Structure-Activity Relationship

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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...

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Related Experiment Video

Updated: Jun 16, 2026

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

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

Published on: February 20, 2018

N-heterocyclic derived M1 positive allosteric modulators.

Scott D Kuduk¹, Christina N Di Marco, Victoria Cofre

¹Department of Medicinal Chemistry, Merck Research Laboratories, Sumneytown Pike, PO Box 4, West Point, PA 19486, USA. scott_d_kuduk@merck.com

Bioorganic & Medicinal Chemistry Letters

|January 26, 2010

Summary

Replacing phenyl rings with N-linked heterocycles in M1 positive allosteric modulators improved drug properties. A pyrazole derivative showed enhanced potency, free fraction, and central nervous system exposure.

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Quantifying Agonist Activity at G Protein-coupled Receptors

Quantifying Agonist Activity at G Protein-coupled Receptors

Published on: December 26, 2011

Area of Science:

Medicinal Chemistry
Neuroscience
Drug Discovery

Background:

Quinolone carboxylic acids are scaffolds for M1 positive allosteric modulators.
Optimizing pharmacokinetic properties is crucial for CNS-acting drugs.

Purpose of the Study:

To investigate the impact of replacing the phenyl ring with N-linked heterocycles in quinolone carboxylic acid M1 positive allosteric modulators.
To identify novel analogs with improved potency and brain penetration.

Main Methods:

Synthesis of novel quinolone carboxylic acid derivatives.
In vitro assays to determine M1 receptor binding and functional activity.
Pharmacokinetic studies to assess free fraction and CNS exposure.

Main Results:

Several N-linked heterocyclic analogs were synthesized and evaluated.
A specific pyrazole derivative demonstrated significant improvements in potency.
This pyrazole analog also exhibited enhanced free fraction and central nervous system (CNS) exposure compared to parent compounds.

Conclusions:

Replacing the phenyl ring with N-linked heterocycles is a viable strategy for optimizing M1 positive allosteric modulators.
The pyrazole derivative represents a promising lead compound for further development targeting M1 receptors.