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Related Concept Videos

Nondepolarizing (Competitive) Neuromuscular Blockers: Mechanism of Action01:17

Nondepolarizing (Competitive) Neuromuscular Blockers: Mechanism of Action

Nondepolarizing neuromuscular blockers induce paralysis by competitively blocking nicotinic acetylcholine receptors at the muscle end plate. Examples include pancuronium, mivacurium, vecuronium, and rocuronium. These quaternary ammonium derivatives are administered intravenously, are poorly absorbed, and are excreted via the kidneys.
Competitive antagonists prevent acetylcholine from binding to its receptor, inhibiting membrane depolarization. Without conformational changes or intrinsic...
Nondepolarizing (Competitive) Neuromuscular Blockers: Pharmacological Actions01:27

Nondepolarizing (Competitive) Neuromuscular Blockers: Pharmacological Actions

Nondepolarizing neuromuscular blockers prevent the membrane depolarization of muscle cells and inhibit muscle contraction. These are usually administered with anesthetics to achieve complete muscle relaxation. Upon administration, these drugs first block the small, rapidly contracting muscles of the face and hands, followed by the larger muscles of the trunk and the intercostal muscles. The diaphragm is the last muscle to be affected.
Although all competitive neuromuscular blockers are designed...
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.
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Dopamine receptor antagonists, also known as antipsychotic agents, are critical in managing chemotherapy-induced vomiting. These antiemetic agents block dopamine receptors in the chemoreceptor trigger zone (CTZ), inhibiting signal transmission to the vomiting center. Antipsychotic agents encompass phenothiazines (PTZ), butyrophenones, benzamides, and thienobenzodiazepines (Zyprexa), which are utilized for their antiemetic and sedative properties.
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Drugs Acting on Autonomic Ganglia: Blockers

Ganglionic blockers inhibit autonomic activity by blocking nicotinic receptors in the autonomic ganglia, suppressing impulse transmission. These blockers lack selectivity between sympathetic and parasympathetic ganglia and are ineffective as neuromuscular junction antagonists. They can be categorized into two groups:
Direct-Acting Cholinergic Agonists: Therapeutic Uses01:11

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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.

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Methods for the Discovery of Novel Compounds Modulating a Gamma-Aminobutyric Acid Receptor Type A Neurotransmission
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Potent benzimidazolone-based CGRP receptor antagonists.

Cory R Theberge1, Rodney A Bednar, Ian M Bell

  • 1Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA. cory_theberge@merck.com

Bioorganic & Medicinal Chemistry Letters
|October 25, 2008
PubMed
Summary

Researchers optimized spirohydantoin CGRP receptor antagonists for potency. The modified compounds effectively blocked CGRP-mediated vasodilation in vivo, correlating with in vitro activity in serum-shifted assays.

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Published on: February 20, 2018

Area of Science:

  • Medicinal Chemistry
  • Pharmacology
  • Neuroscience

Background:

  • Calcitonin gene-related peptide (CGRP) antagonists are investigated for therapeutic potential.
  • Spirohydantoin scaffolds have shown promise as CGRP receptor antagonists.
  • Optimization of existing drug scaffolds is crucial for enhancing efficacy and reducing off-target effects.

Purpose of the Study:

  • To optimize the potency of spirohydantoin-based CGRP receptor antagonists.
  • To identify compounds with maintained in vitro activity in the presence of human serum.
  • To evaluate the in vivo efficacy of optimized compounds in blocking CGRP-mediated vasodilation.

Main Methods:

  • Modification of benzimidazolone substituents on spirohydantoin scaffolds.
  • In vitro functional assays measuring cAMP levels in the presence of 50% human serum.
  • In vivo pharmacodynamic assays in rhesus models to assess blockade of CGRP-mediated vasodilation.

Main Results:

  • Optimized spirohydantoin compounds demonstrated enhanced potency.
  • Identified compounds exhibited minimal reduction in activity in serum-shifted functional assays.
  • In vivo studies confirmed blockade of CGRP-mediated vasodilation, with potency correlating to in vitro serum-shifted assay results.

Conclusions:

  • Modification of benzimidazolone substituents effectively optimized spirohydantoin CGRP antagonists.
  • The developed compounds maintain in vitro efficacy in a relevant biological matrix.
  • These optimized antagonists show promising in vivo activity for potential therapeutic applications.