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Related Concept Videos

Indirect-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship01:29

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

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Indirect-acting cholinergic agonists are agents that interact with the acetylcholinesterase enzyme in the synaptic cleft, preventing the breakdown of acetylcholine into choline and acetate. Consequently, the concentration of acetylcholine in the synaptic cleft increases. These agonists can be classified into reversible and irreversible inhibitors based on their duration of action.
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Direct-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship01:22

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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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Indirect-Acting Cholinergic Agonists: Mechanism of Action01:18

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Indirect-acting cholinergic agonists work by interacting with an enzyme called acetylcholinesterase (AChE) in the synaptic cleft. They can be reversible or irreversible inhibitors and have different effects on the enzyme.
Reversible inhibitors like edrophonium bind to a specific part of the enzyme called the anionic catalytic site. They form noncovalent bonds, which means they are not strongly attached to the enzyme. This creates a temporary and less stable enzyme–inhibitor complex,...
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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.
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Adrenergic Agonists: Chemistry and Structure-Activity Relationship01:16

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Adrenergic agonists' structure-activity relationship (SAR) determines their selectivity and efficacy. These agonists comprise a phenylethylamine moiety with an aromatic ring and an ethylamine side chain.
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Separation of...
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Local Anesthetics: Chemistry and Structure-Activity Relationship01:27

Local Anesthetics: Chemistry and Structure-Activity Relationship

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Local anesthetics (LAs) are drugs that induce a temporary loss of sensation in a limited body area, preventing pain. Cocaine was the first local anesthetic discovered in the late 19th century. Cocaine is a benzoic acid ester obtained from the leaves of coca shrubs and was often used for its psychotropic effects. Cocaine was first isolated in 1860 by Albert Niemann. Sigmund Freud studied the physiological actions of cocaine. Carl Koller later introduced it into clinical practice in 1884 as a...
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2',4'-LNA-Functionalized 5'-S-Phosphorothioester CDNs as STING Agonists.

Simpa K Yeboah1,2, Abdulai Zigli1,2, Herman O Sintim1,2,3

  • 1Department of Chemistry, 560 Oval Drive, West Lafayette, Indiana, 47907-2084.

Chembiochem : a European Journal of Chemical Biology
|May 9, 2024
PubMed
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New locked nucleic acid-functionalized cyclic dinucleotides (LNA endo-S-CDNs) show potential as immunotherapeutics. These compounds activate the cGAS-STING pathway and exhibit enhanced chemical and enzymatic stability for cancer vaccines.

Keywords:
5’-S-phosphorothioesterCyclic DinucleotidePDESTING AgonistcGAMPhydrolytically stablephosphorothioate

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Area of Science:

  • Immunology
  • Medicinal Chemistry
  • Biochemistry

Background:

  • Cyclic dinucleotides (CDNs) activate the cGAS-STING pathway, crucial for innate and adaptive immunity.
  • CDN analogs are explored as cancer vaccines and immunomodulators, but face limitations due to chemical and enzymatic instability.
  • Previous work introduced phosphorothioate analogs with improved stability against phosphodiesterases.

Purpose of the Study:

  • To synthesize and evaluate locked nucleic acid-functionalized (LNA) endo-S-CDNs as STING agonists.
  • To assess the stability and immune-activating potential of these novel CDN analogs.
  • To investigate their efficacy in activating STING, particularly in cell lines with diminished responses.

Main Methods:

  • Synthesis of LNA-functionalized endo-S-CDNs.
  • Activation assays of the human STING (hSTING) pathway in THP1 monocytes.
  • Evaluation of chemical stability against oxidants (I2, H2O2) and enzymatic stability against phosphodiesterases.

Main Results:

  • Some synthesized LNA 3'3'-endo-S-CDNs moderately activated hSTING (REF haplotype R232H).
  • This activation was observed in a cell line with reduced responsiveness to standard STING agonists like 2'3'-cGAMP and ADU-S100.
  • One potent endo-S-CDN analog demonstrated significant chemical and phosphodiesterase stability.

Conclusions:

  • LNA endo-S-CDNs represent a promising class of STING agonists with enhanced stability.
  • These novel compounds may overcome limitations of existing CDNs, offering potential for improved immunotherapeutics.
  • Further research into LNA endo-S-CDNs could advance cancer vaccine and immunotherapy development.