Abstract

We have characterized the pharmacological antagonism, i.e., neutral antagonism or inverse agonism, displayed by a number of α-blockers at two α1-adrenergic receptor (AR) subtypes, α_1a- and α_1b-AR. Constitutively activating mutations were introduced into the α_1a-AR at the position homologous to A293 of the α_1b-AR where activating mutations were previously described. Twenty-four α-blockers differing in their chemical structures were initially tested for their effect on the agonist-independent inositol phosphate response mediated by the constitutively active A271E and A293E mutants expressed in COS-7 cells. A selected number of drugs also were tested for their effect on the small, but measurable spontaneous activity of the wild-type α_1a- and α_1b-AR expressed in COS-7 cells. The results of our study demonstrate that a large number of structurally different α-blockers display profound negative efficacy at both the α_1a- and α_1b-AR subtypes. For other drugs, the negative efficacy varied at the different constitutively active mutants. The most striking difference concerns a group of N-arylpiperazines, including 8-[2-[4-(5-chloro-2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4,5] decane-7,9-dione (REC 15/3039), REC 15/2739, and REC 15/3011, which are inverse agonists with profound negative efficacy at the wild-type α_1b-AR, but not at the α_1a-AR.