U-50,488H, a kappa (kappa) opioid ligand with moderate potency at sigma (sigma) receptors, protects against mechanical and ischemia-induced injury. The purpose of this study was to evaluate the possibility that sigma-receptors may be involved in mediating the neuroprotective actions of U-50,488H. This possibility was examined by testing the potential of a series of U-50,488H analogs, which are potent sigma-ligands with minimal activity at kappa-opioid receptors, to protect against ischemia-induced neuronal damage in the gerbil. Like U-50,488H, BD-449 (20 mg/kg), the cis-diastereomer of U-50,4888H, protected against ischemia-induced neuronal damage as did BD-737 (50 and 30 mg/kg) and BD-738 (50 mg/kg). All 3 compounds interacted selectively with sigma-receptors. In contrast, BD-601 (50 mg/kg), did not protect against ischemia-induced neuronal damage, although it also interacted potently with sigma-receptors. One difference between the compounds that were neuroprotective and BD-601 is that only BD-601 produced sigma-like behavioral effects in the rat. Thus, it is possible that BD-601 may interact differently or at a different sigma-subtype than BD-449, BD-737 and BD-738 with sigma-receptors. However, these results clearly indicate that an interaction with kappa-opioid receptors is not required for anti-ischemic activity, and that sigma-receptors may play a role in neuroprotection.

The synthetic prostaglandin misoprostol was found to enhance the immunosuppressive effects of cyclosporine A in vitro on human peripheral lymphocytes and mouse spleen cells, by synergizing with the latter drug, although on its own misoprostol was not potent as an immunosuppressive. These results suggest the possibility of exploiting the use of synthetic prostaglandins as adjunctive therapy in preventing clinical transplant rejection.