TY - JOUR T1 - Inverse Agonism and Neutral Antagonism at α<sub>1a</sub>- and α<sub>1b</sub>-Adrenergic Receptor Subtypes JF - Molecular Pharmacology JO - Mol Pharmacol SP - 858 LP - 866 DO - 10.1124/mol.56.5.858 VL - 56 IS - 5 AU - Olivier Rossier AU - Liliane Abuin AU - Francesca Fanelli AU - Amedeo Leonardi AU - Susanna Cotecchia Y1 - 1999/11/01 UR - http://molpharm.aspetjournals.org/content/56/5/858.abstract N2 - 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, α1a- and α1b-AR. Constitutively activating mutations were introduced into the α1a-AR at the position homologous to A293 of the α1b-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 α1a- and α1b-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 α1a- and α1b-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 α1b-AR, but not at the α1a-AR. ER -