Inverse Agonism and Neutral Antagonism at α1a- and α1b-Adrenergic Receptor Subtypes
- 1Institute of Pharmacology and Toxicology, Université de Lausanne, Lausanne, Switzerland (O.R., L.A., S.C.); 2Department of Chemistry, Università di Modena e Reggio Emilia, Modena, Italy (F.F.); and 3Pharmaceutical R&D Division, Recordati S.p.A., Milan, Italy (A.L.)
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, 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.
Footnotes
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Send reprint requests to: Susanna Cotecchia, M.D., Institut de Pharmacologie et de Toxicologie, 27, Rue du Bugnon, Faculté de Médecine, 1005 Lausanne, Switzerland. E-mail:susanna.cotecchia{at}ipharm.unil.ch
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This work was supported by the Fonds National Suisse de la Recherche Scientifique (Grant 31-51043.97) and by the European Community (Grant BMH4-CT97-2152).
- Abbreviations:
- AR
- adrenergic receptor
- GPCR
- G protein-coupled receptor
- DMEM
- Dulbecco’s modified Eagle’s medium
- [125I]HEAT
- [125I]iodo-2-[β-(4-hydroxyphenyl)-ethyl-aminomethyl]tetralone
- IP
- inositol phosphate
- CAM
- constitutively active mutant
- R
- inactive
- R*
- active
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- Received April 21, 1999.
- Accepted July 28, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
