Binding of umespirone to the sigma receptor: evidence for multiple affinity states

Umespirone (3,7-diazabicyclo[3.3.1]nonane-2,4,6,8-tetraon; KC9172) has been recently described as a potential antipsychotic/anxiolytic. In the present study the interaction of umespirone and several other typical and atypical psychotropics with the sigma and phencyclidine (PCP) receptor subtypes, in rat brain membranes, was investigated. Umespirone, haloperidol, chlorpromazine and buspirone, but not clozapine and diazepam, compete for the binding of the sigma-ligand, (+)[3H]-3-(3-hydroxy-phenyl)-N-1-(propyl) piperidine [(+)]3H-3-PPP]. The compounds do not compete for the binding of PCP-receptor ligands. Umespirone, buspirone and (+)-3-PPP, unlike haloperidol and chlorpromazine, inhibit (+)[3H]-3-PPP binding in a manner indicating the existence of high and low affinity states of the sigma receptor. 5'-Guanylylimidodiphosphate (Gpp(NH)p; 0.1mM) abolishes the high affinity binding component associated with the binding of umespirone, buspirone and (+)-3-PPP, but does not affect the affinities of haloperidol and chlorpromazine for the sigma receptor. These findings suggest that different coupling states of the sigma receptor may be associated with the binding of umespirone and buspirone compared to the binding of haloperidol and chlorpromazine.