Sigma receptors are targets for haloperidol and related antipsychotics. Although these drugs have found enormous clinical utility, they elicit severe side effects in a large percentage of patients. The long-term goal of this proposal is to develop a new generation of sigma subtype, selective compounds with clinical utility. We have recently obtained access to a novel sigma l-selective iodinated radioligand that opens up, for the first time, the possibility of expression-cloning sigma receptors. In this Phase I application, we will use this novel compound to expression-clone this sigma-l receptor from a cDNA library made from a cell line shown to have a very high density of these receptors. In Phase II, the sequence will be used for cloning related sigma receptor subtypes, and these genes will be stably expressed in mammalian cells. These transfected cells will be used in a drug discovery program aimed at developing improved antipsychotics and other sigma-selective pharmaceuticals.National Institute of Mental Health (NIMH)
