RT Journal Article SR Electronic T1 Inverse Agonism and Neutral Antagonism at α1a- and α1b-Adrenergic Receptor Subtypes JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 858 OP 866 DO 10.1124/mol.56.5.858 VO 56 IS 5 A1 Olivier Rossier A1 Liliane Abuin A1 Francesca Fanelli A1 Amedeo Leonardi A1 Susanna Cotecchia YR 1999 UL http://molpharm.aspetjournals.org/content/56/5/858.abstract AB 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.