Sigma receptors are saturable, high affinity binding sites for several important classes of psychotropic drugs including typical antipsychotic, antidepressant, anticonvulsant, and psychotomimetic compounds. Sigma sites are located not only in the central nervous system, but also occur in high density in several peripheral tissues, including liver, kidney, intestine, and endocrine tissue, suggesting important functional roles of these receptors. They are likely to contribute to the beneficial and/or side-effect profile of these compounds. Our unit has investigated several aspects of the molecular and cellular pharmacology of sigma receptors. Identification of a novel subtype of sigma-1 receptor: Sigma receptors exist in a least two major subtypes, sigma-1 and sigma-2. C6 glioma and some other clonal cell lines were found to possess a sigma-1 site (labeled by [3H](+)-pentazocine) which exhibits subtle differences from the sigma-1 site of guinea pig brain. Lower benzomorphan enantio- selectivity and higher calcium ion sensitivity distinguish it from sites of guinea pig brain. This suggests heterogeneity of sigma-1 sites, and may have important functional implications (see below). Sigma receptor-mediated cytotoxicity: Sigma ligands exhibit high affinity for most typical neuroleptic drugs, including haloperidol. Haloperidol, its metabolites, and several other sigma-active neuroleptics were found to alter the morphology and viability of C6 glioma cells in culture. The compounds caused withdrawal of processes, rounding, and ultimately cell death. Neuroleptics and other compounds which lack affinity for sigma sites had no effect on cells. These effects appear to be mediated by a novel subtype of sigma-1 site identified in C6 glioma and other cell lines. The results suggest that sigma receptors, present in high concentrations in brain motor nuclei, might mediate toxic alterations in cells upon chronic exposure to neuroleptics. This might in turn contribute to irreversible neuroleptic-induced motor abnormalities such as tardive dyskinesia. The data also suggest a possible role of sigma receptors in idiopathic neurodegenerative disorders. Development of novel sigma agonists and antagonists: Activation of sigma-1 receptors inhibits the ability of muscarinic agonists to stimulate phosphoinositide turnover in brain. Sigma inhibition of the muscarinic (oxotremorine-M) phosphoinositide response was used as a functional assay to screen novel compounds. Despite high sigma binding affinity, several novel ethylenediamines, piperazines, and polyamines exhibited low efficacy, suggesting that they were antagonists or partial agonists. BD1139, a partial agonist, was shown to attenuate the ability of (+)-pentazocine to inhibit oxotremorine-M stimulation. Two other compounds, BD1047 and BD1063 were identified and are being investigated as possible full sigma-1 antagonists. These compounds will be extremely useful for functional studies of sigma sites and have potential therapeutic value.