The sigma receptor was originally described as one of the subtypes of the opioid receptors mediating the hallucinogenic effects of certain synthetic benzomorphan type opiate drugs. While the behavioral effects of putative sigma receptor active drugs have been relatively well characterized, it has been difficult to characterize the sigma receptor by in vitro receptor binding experiments. This is due to the lack of selective drug ligands that do not crossreact with other (mu, delta, kappa) opioid receptors. We have recently discovered a new class of highly selective and potent sigma receptor active drugs. We have prepared a tritium labeled derivative of one of these compounds ([3H]1,3-di-o-tolyl-guanidine) ([3H]DTG). Using this novel, selective sigma receptor ligand we have performed extensive characterization studies on the drug selectivity of the sigma receptor and on its distribution in brain tissue. We find that the sigma receptor not only binds all hallucinogenic benzomorphan type drugs, but that it also binds with high affinity most antipsychotic drugs, particularly haloperidol. This drug selectivity profile makes the sigma receptor a good candidate to be involved in the biochemical origin of mental illness, particularly schizophrenia. The purification of the sigma receptor and the cloning of its gene may provide new insights into the poorly understood area of biochemical basis of mental illness. In this application we are requesting funds for the development of alkylating derivatives of DTG that are radioactively labeled with either [3H] or 125I. We intend to use these alkylating derivatives as affinity ligands to covalently label the sigma receptor in brain membranes. Availability of a radioactively labeled, irreversible ligand for the sigma receptor will greatly facilitate its purification from brain membrane extracts.
