An unambiguous assay for the cloned human sigma1 receptor reveals high affinity interactions with dopamine D4 receptor selective compounds and a distinct structure-affinity relationship for butyrophenones

Ivan T. Lee, Shiuhwei Chen, John A. Schetz

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

The ability of the sigma1 receptor to interact with a huge range of drug structural classes coupled with its wide distribution in the body has contributed to it being implicated as a possible therapeutic target for a broad array of disorders ranging from substance abuse to depression to Alzheimer's disease. Surprisingly, the reported affinity values for some sigma1 receptor ligands vary more than 50-fold. The potential of the sigma1 receptor as a pharmacotherapeutic target prompted us to develop an unambiguous assay system for measuring the affinity of ligands to the cloned human sigma1 receptor. In the course of characterizing this system and determining the true affinity values for almost three dozen compounds, it was discovered that some dopamine D4 receptor selective compounds bind sigma1 receptors with high affinity. A systematic analysis of haloperidol-like compounds revealed a clear structure-affinity relationship amongst clinically relevant butyrophenones. The antidepressant fluvoxamine, the drug of abuse methamphetamine, and the neurosteroid progesterone were amongst the many ligands whose interactions with the sigma1 receptor were confirmed with our screening assay.

Original languageEnglish
Pages (from-to)123-136
Number of pages14
JournalEuropean Journal of Pharmacology
Volume578
Issue number2-3
DOIs
StatePublished - 14 Jan 2008

Keywords

  • Antipsychotics
  • N-methyl-d-aspartate receptor
  • Neuroprotection
  • Opioid receptor
  • Psychostimulants
  • Psychotomimetics

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