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

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.