Binding of umespirone to the σ 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 o 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 σ-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 a 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 o receptor. These findings suggest that different coupling states of the o receptor may be associated with the binding of umespirone and buspirone compared to the binding of haloperidol and chlorpromazine.