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Related Experiment Videos

Structural determinants of sigma receptor affinity.

B L Largent1, H Wikström, A L Gundlach

  • 1Department of Neuroscience, Johns Hopkins University, School of Medicine, Baltimore, Maryland 21205.

Molecular Pharmacology
|December 1, 1987
PubMed
Summary

Structural analysis reveals that sigma receptor affinity differs significantly from opiate receptor binding. Lipophilic N-substituents and phenylpiperidine moieties are key for high sigma receptor affinity.

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Area of Science:

  • Pharmacology
  • Medicinal Chemistry
  • Neuroscience

Background:

  • Sigma receptors are a class of receptors distinct from classical opiate receptors.
  • Understanding the structural basis of ligand binding to sigma receptors is crucial for drug development.

Purpose of the Study:

  • To investigate the structural determinants of sigma receptor affinity.
  • To identify common pharmacophores responsible for high affinity binding to sigma receptors.

Main Methods:

  • Evaluation of a diverse range of compounds, including opioids, neuroleptics, and phenylpiperidine derivatives.
  • Radioligand binding assays using (+)-[3H]3-PPP to label sigma receptor sites.
  • Conformational calculations to assess structural-ligand interactions.

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Main Results:

  • Sigma receptor affinity requirements differ from opiate receptors, showing reverse stereoselectivity.
  • Opioid compounds with higher lipophilicity and lacking the C ring (benzomorphans) exhibit greater sigma receptor affinity.
  • Haloperidol, a butyrophenone, demonstrated the highest potency at sigma receptors.
  • The 4-phenylpiperidine moiety and lipophilic N-substituents are critical for high affinity.

Conclusions:

  • A phenylpiperidine structure with a lipophilic N-substituent represents a common pharmacophore for high sigma receptor affinity.
  • Structural diversity is tolerated, provided key pharmacophoric elements are present.
  • Findings provide insights into the design of novel sigma receptor ligands.