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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

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.
Reversible inhibitors display short to medium durations of action. Short-acting agents include simple alcohols with...
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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: Jul 17, 2026

Facile Preparation of 4-Substituted Quinazoline Derivatives
11:51

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Published on: February 15, 2016

5-HT3 receptor antagonists. 1. New quinoline derivatives.

H Hayashi1, Y Miwa, I Miki

  • 1Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka-ken, Japan.

Journal of Medicinal Chemistry
|December 25, 1992
PubMed
Summary

New quinoline derivatives show high affinity for serotonin 5-HT3 receptors, with some esters being significantly more potent than ondansetron. These compounds may interact differently with 5-HT3 receptors, suggesting potential therapeutic applications.

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Area of Science:

  • Medicinal Chemistry
  • Neuropharmacology
  • Molecular Modeling

Background:

  • Serotonin 5-HT3 receptors are crucial targets for treating conditions like nausea and vomiting.
  • Existing 5-HT3 receptor antagonists, such as ondansetron, have established therapeutic roles.
  • Understanding structure-activity relationships is key to developing novel and more effective antagonists.

Purpose of the Study:

  • To synthesize and evaluate novel quinoline derivatives for their affinity to serotonin 5-HT3 receptors.
  • To investigate the impact of structural modifications, including lipophilic substituents and moiety types (ester vs. amide), on receptor binding.
  • To explore the in vivo activity of these compounds using the Bezold-Jarisch reflex test and correlate it with receptor affinity.

Main Methods:

  • Synthesis of a series of esters and amides of quinoline carboxylic acids with a basic azabicycloalkyl moiety.
  • Radioligand binding assays using [3H]quipazine to determine the affinity (Ki values) for 5-HT3 receptors.
  • Molecular modeling studies to analyze the spatial orientation of key functional groups.
  • In vivo evaluation of selected compounds in the Bezold-Jarisch reflex test.

Main Results:

  • Most synthesized esters demonstrated significantly higher affinity for 5-HT3 receptors compared to ondansetron (Ki = 7.6 nM).
  • Compounds 21 and 37 exhibited the highest affinities, with Ki values of 0.32 nM and 0.31 nM, respectively.
  • Lipophilic substituents on the quinoline ring generally enhanced receptor affinity.
  • Amide derivatives showed considerably lower affinity (approximately 100-fold) compared to their ester counterparts.
  • Molecular modeling revealed non-planar conformations for the carbonyl moiety in some compounds.
  • A lack of strong correlation was observed between in vitro 5-HT3 receptor affinity and in vivo activity in the Bezold-Jarisch reflex test.

Conclusions:

  • The synthesized quinoline derivatives, particularly esters with lipophilic substituents, represent potent ligands for serotonin 5-HT3 receptors.
  • The observed discrepancies between in vitro affinity and in vivo activity suggest potential differences in receptor interactions or the involvement of receptor subtypes.
  • These findings may indicate heterogeneity of 5-HT3 receptors in the brain and heart, influencing drug response.
  • The developed quinoline derivatives hold promise as novel therapeutic agents, warranting further investigation into their specific mechanisms and therapeutic potential.