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Drugs Acting on Autonomic Ganglia: Blockers01:28

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Depolarizing blockers act on skeletal muscle fibers' membranes and induce their depolarization. Most depolarizing blockers have two quaternary N+ atoms that bind the nicotinic acetylcholine receptors and cause neuromuscular blockade within minutes.
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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.
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Depolarizing blockers are administered through intravenous injection. Succinylcholine is the most common choice of depolarizing blockers in emergency clinical practices. Although they have a rapid onset, they readily diffuse away from the motor end plate into the extracellular fluid. They are metabolized by enzymes such as liver butyrylcholinesterase and plasma pseudocholinesterases. This produces a short duration of action, typically 5-10 minutes long, unlike nondepolarizing blockers, which...
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hERG Blockade by Iboga Alkaloids.

Kenneth Alper1, Rong Bai2, Nian Liu2

  • 1Departments of Psychiatry and Neurology, New York University School of Medicine, New York, NY, 10016, USA.

Cardiovascular Toxicology
|February 1, 2015
PubMed
Summary
This summary is machine-generated.

Ibogaine and its metabolite noribogaine block the hERG channel, potentially causing cardiac issues. A synthetic derivative, 18-methoxycoronaridine, shows significantly reduced hERG channel blockade, offering a safer alternative for addiction treatment.

Keywords:
18-Methoxycoronaridine (18-MC)Iboga alkaloidIbogaineNoribogaineToxicologyhERG

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Area of Science:

  • Pharmacology
  • Cardiovascular Science
  • Medicinal Chemistry

Background:

  • Iboga alkaloids, including ibogaine, are used clinically for addiction treatment.
  • Ibogaine is associated with serious cardiac side effects like QT prolongation and fatalities.
  • The hERG channel (IKr) is a key target for understanding drug-induced cardiotoxicity.

Purpose of the Study:

  • To investigate the hERG channel blockade activity of ibogaine, its metabolite noribogaine, and related compounds.
  • To compare the hERG channel interaction of naturally derived alkaloids with a rationally synthesized derivative, 18-methoxycoronaridine (18-MC).
  • To explore structure-activity relationships for iboga alkaloids concerning hERG channel blockade.

Main Methods:

  • Whole-cell patch clamp technique in HEK 293 cells to measure hERG channel blockade (IKr).
  • Determination of IC50 values for ibogaine, noribogaine, voacangine, and 18-methoxycoronaridine.
  • Measurement of hERG channel binding affinities (Ki) for the tested compounds.

Main Results:

  • Ibogaine, noribogaine, and voacangine demonstrated significant hERG channel blockade with IC50 values in the low micromolar range.
  • 18-methoxycoronaridine exhibited markedly reduced hERG channel blockade, with an IC50 >50 µM.
  • All compounds showed voltage-dependent hERG blockade, indicative of low-affinity interactions, with 18-MC binding similarly but causing less blockade.

Conclusions:

  • Noribogaine's extended half-life and hERG blockade may explain persistent cardiac risks after ibogaine use.
  • 18-methoxycoronaridine represents a potentially safer iboga alkaloid derivative due to its significantly lower hERG channel blockade.
  • Structure-activity relationships suggest iboga alkaloids can inform hERG channel structural biology research.