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Vol. 56, Issue 5, 858-866, November 1999
1a-
and 1b-Adrenergic Receptor Subtypes
Institute of Pharmacology and Toxicology, Université de
Lausanne, Lausanne, Switzerland (O.R., L.A., S.C.); Department of
Chemistry, Università di Modena e Reggio Emilia, Modena, Italy
(F.F.); and Pharmaceutical R&D Division, Recordati S.p.A., Milan, Italy
(A.L.)
We have characterized the pharmacological antagonism, i.e., neutral
antagonism or inverse agonism, displayed by a number of 
-blockers at
two 1-adrenergic receptor (AR) subtypes, 1a- and 1b-AR. Constitutively activating mutations were
introduced into the 1a-AR at the position homologous to
A293 of the 1b-AR where activating mutations were
previously described. Twenty-four -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
1a- and 1b-AR expressed in COS-7 cells. The results of our study demonstrate that a large number of
structurally different -blockers display profound negative efficacy
at both the 1a- and 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 1b-AR, but not at the
1a-AR.
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