title: Inverse agonism and neutral antagonism at alpha(1a)- and alpha(1b)-adrenergic receptor subtypes.
abstract: We have characterized the pharmacological antagonism, i.e., neutral antagonism or inverse agonism, displayed by a number of alpha-blockers at two alpha1-adrenergic receptor (AR) subtypes, alpha(1a)- and alpha(1b)-AR. Constitutively activating mutations were introduced into the alpha(1a)-AR at the position homologous to A293 of the alpha(1b)-AR where activating mutations were previously described. Twenty-four alpha-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 alpha(1a)- and alpha(1b)-AR expressed in COS-7 cells. The results of our study demonstrate that a large number of structurally different alpha-blockers display profound negative efficacy at both the alpha(1a)- and alpha(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 alpha(1b)-AR, but not at the alpha(1a)-AR.
authors.affiliation: Institute of Pharmacology and Toxicology, Université de Lausanne, Lausanne, Switzerland.
authors.forename: O
authors.initials: O
authors.lastname: Rossier
authors.forename: L
authors.initials: L
authors.lastname: Abuin
authors.forename: F
authors.initials: F
authors.lastname: Fanelli
authors.forename: A
authors.initials: A
authors.lastname: Leonardi
authors.forename: S
authors.initials: S
authors.lastname: Cotecchia
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D019556:COS Cells; D006224:Cricetinae; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D016296:Mutagenesis; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: C547713:ADRA1A protein, human; C547716:ADRA1B protein, human; D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D007295:Inositol Phosphates; D008024:Ligands; D018340:Receptors, Adrenergic, alpha-1