DUP-734

So far, sigma-ligands have been investigated for several indications in human studies in functional diarrhea as a model of somatoform disorder (igmesine), depression (igmesine, opipramol), anxiety (opipramol and--in animal models--siramisine), schizophrenia (panamasine, SL 82.0715, rimcazole, DuP 734, BMY 14 802), and somatoform disorders (opipramol). Results for schizophrenia failed to be clear cut and so investigations have apparently stopped for the time being. The Sigma-1-selective igmesine (200 mg) showed good results in a phase-1-model of functional diarrhea and some promising results in depressed patients. However, further development has been stopped due to marketing reasons, which is also true for siramasine, a selective sigma-2-ligand with anxiolytic properties. Opipramol, which, apart from a sigma-1- and 2-receptor liability, also possesses histamine-H(1)-antagonistic properties in connection with lower affinities for D(2) and 5-HT(2A) showed broad efficacy in generalized anxiety disorder and somatoform disorders. The receptor profile of opipramol and the results of studies of the selective sigma site ligands siramisine and igmesine suggest that opipramol acts pharmacologically and clinically via sigma receptors.

It has been suggested that neuropeptide Y (NPY) and sigma (sigma) receptor ligands may share a putative NPY/sigma receptor in rat brain. To study whether NPY and sigma receptor ligands have an inverse agonism at this putative NPY/sigma receptor, we measured their effects on G-protein activity in rat brain. Using [35S]GTPgammaS autoradiography, we found that NPY-induced G-protein activation exhibited a discrete distribution pattern in rat brain. G-protein activation in superficial cortical layers and hippocampal CA1-3 region was mainly attributed to Y1 and Y2 receptors, respectively. In the presence of 10 microM sigma-receptor agonist BD737 or 10 microM sigma-receptor antagonist haloperidol, the distribution and density of [35S]GTPgammaS binding stimulated by 10 nM NPY was not significantly altered. In rat cerebellar membranes, NPY stimulated high-affinity GTPase activity in a dose-related manner, with maximal effects of 29% increase over basal level seen at 500 nM. This NPY-elicited GTPase activity was not significantly affected by micromolar concentrations of the sigma-receptor antagonists Dup734 or haloperidol. Since no significant effects by sigma-receptor ligands on NPY-induced G-protein activation were observed, we did not see an inverse agonism of NPY and sigma-receptor ligands at the putative NPY/sigma receptor measured at the level of G-protein activation, suggesting that sigma receptors and NPY receptors do not represent a common population in rat hippocampus and cerebellum. It is also suggested that G-protein activation is not a convergent point for the signal transduction mechanisms of NPY receptors and sigma receptors.