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Hallucinogens and serotonergic mechanisms.

R A Glennon1, M Teitler, E Sanders-Bush

  • 1Department of Medicinal Chemistry, Medical College of Virginia/Virginia Commonwealth University, Richmond 23298.

NIDA Research Monograph
|January 1, 1992
PubMed
Summary

Classical hallucinogens are agonists that bind to serotonin 5-HT2 receptors. Their hallucinogenic potency correlates with this binding affinity, suggesting partial agonism may cause hallucinations.

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Area of Science:

  • Neuroscience
  • Pharmacology
  • Medicinal Chemistry

Background:

  • Classical hallucinogens exhibit serotonin 5-HT2 receptor agonist activity.
  • Antagonists at this receptor lack hallucinogenic effects.
  • Previous studies correlated hallucinogenic potency with 5-HT2 receptor affinity using [3H]-ketanserin.

Purpose of the Study:

  • To investigate the relationship between 5-HT2 receptor affinity and the hallucinogenic potency of classical hallucinogens and related agents.
  • To explore the role of radioligand choice ([3H]-ketanserin vs. [3H]DOB) in characterizing receptor binding.
  • To model the affinity of DOB-related agents based on substituent properties.

Main Methods:

  • Radioligand binding assays using [3H]-ketanserin and [3H]DOB to determine 5-HT2 receptor affinity.
  • Analysis of structure-activity relationships for a series of DOB-related compounds.
  • Correlation of binding affinities with hallucinogenic potencies and lipophilicity.

Main Results:

  • Hallucinogenic potency of agonists correlates with 5-HT2 receptor affinity, particularly when using [3H]DOB, which labels the high-affinity agonist state.
  • For DOB analogs, 5-HT2(KET) affinity is influenced by the lipophilicity of the 4-position substituent.
  • 5-HT2 affinity, when using [3H]DOB, is related to both lipophilicity and electron-withdrawing properties of the 4-position substituent.
  • Differences in binding between [3H]-ketanserin and [3H]DOB may reflect intrinsic activity.

Conclusions:

  • Hallucinogenic effects of classical hallucinogens are strongly linked to their high-affinity binding as partial agonists at serotonin 5-HT2 receptors.
  • Structural features, including lipophilicity and electronic properties of substituents, modulate 5-HT2 receptor affinity.
  • The intrinsic activity of a compound at the 5-HT2 receptor is a critical determinant of its hallucinogenic potential, distinguishing it from non-hallucinogenic serotonin.

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