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Related Concept Videos

Cholinergic Receptors: Muscarinic01:25

Cholinergic Receptors: Muscarinic

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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+....
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Allosteric Regulation01:08

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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The Two-State Receptor Model01:29

The Two-State Receptor Model

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The two-state receptor model explains a drug's interaction with receptors, such as G protein-coupled receptors and ligand-gated ion channels, to induce or inhibit a biological response. When no natural ligands are present, a receptor exists in an equilibrium of inactive (Ri) and active (Ra) conformations. The inactive form does not produce a response, while the active form generates a basal effect known as constitutive activity.
The binding affinity of a drug determines its interaction with...
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Drug-Receptor Interaction: Agonist01:25

Drug-Receptor Interaction: Agonist

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Agonists are drugs that interact with specific receptors in the body to produce a biological response. When an agonist binds to a receptor, it activates or enhances the receptor's function, leading to physiological effects. The interaction between agonist drugs and receptors is crucial for their therapeutic action in various medical treatments.
Agonists can bind to receptors in different ways. Some agonists bind directly to the receptor's active site, mimicking the endogenous...
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Direct-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship01:22

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

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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...
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Opioid Receptors: Overview01:22

Opioid Receptors: Overview

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Opioid receptors, including the mu (μ, MOR), delta (δ, DOR), and kappa (κ, KOR) types, belong to the rhodopsin family of G protein-coupled receptors. These receptors are located throughout the central and peripheral nervous systems and in non-neuronal tissues such as macrophages and astrocytes. Opioid receptor ligands can be categorized into agonists or antagonists. Highly selective agonists include [d-Ala2, MePhe4, Gly(ol)5]-enkephalin or DAMGO for MOR, [D-Pen2,...
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Related Experiment Video

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Methods for the Discovery of Novel Compounds Modulating a Gamma-Aminobutyric Acid Receptor Type A Neurotransmission
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M1 receptor positive allosteric modulators discovery approaches.

Takao Mandai1, Arthur A Simen2, Antonio Laurenza2

  • 1Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.

Trends in Pharmacological Sciences
|March 25, 2025
PubMed
Summary

Developing M1 muscarinic acetylcholine receptor modulators for cognitive enhancement faces challenges. This study explores novel strategies, low intrinsic agonism and binding cooperativity, to improve efficacy and reduce side effects.

Keywords:
M1 muscarinic acetylcholine receptor (M1R)TAK-071cholinergic adverse eventscognitive enhancementpositive allosteric modulator (PAM)preclinical and clinical characterization

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Area of Science:

  • Neuroscience
  • Pharmacology
  • Medicinal Chemistry

Background:

  • M1 muscarinic acetylcholine receptor (mAChR) positive allosteric modulators (PAMs) show promise for cognitive disorders.
  • Development is hampered by insufficient cognitive effects and undesirable cholinergic side effects.

Purpose of the Study:

  • To explore novel strategies for developing effective and safe M1 mAChR PAMs.
  • To address limitations in cognitive efficacy and cholinergic side effects of current M1 mAChR PAMs.

Main Methods:

  • Investigated compounds with low intrinsic agonism at the M1 mAChR.
  • Examined the role of low binding cooperativity in M1 mAChR PAMs.

Main Results:

  • Low intrinsic agonism strategies show potential for improved therapeutic profiles.
  • Low binding cooperativity may offer a way to dissociate desired from undesired effects.

Conclusions:

  • Novel M1 mAChR PAMs with low intrinsic agonism and binding cooperativity represent a promising therapeutic avenue.
  • These approaches could lead to safer and more effective treatments for cognitive impairments.