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ARDB |
Receptor
Mutation Detail Information |
| Receptor
Name: |
A1AA_HUMAN |
| Mutation
Type: |
Point Mutation |
| Mutation
Class: |
Single |
Mutation Site: |
271 |
| Original AA: |
Ala |
| Mutation
Result: |
Glu |
| Mutation
Domain: |
Mutation
Occurs at ICL3 of the Receptor. |
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| Related
Reference: |
Pubmed ID: 10531388 |
| Detail
Description : |
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. |
| Work
Group : |
Institute of Pharmacology and Toxicology, Université de Lausanne, Lausanne, Switzerland. |
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