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A quantitative analysis of antagonism and inverse agonism at wild-type and constitutively active hamster α1B-adrenoceptors

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Abstract.

In order to characterize inverse agonism at α1B-adrenoceptors, we have compared the concentration-response relationships of several quinazoline and non-quinazoline α1-adrenoceptor antagonists at cloned hamster wild-type (WT) α1B-adrenoceptors and a constitutively active mutant (CAM) thereof upon stable expression in Rat-1 fibroblasts. Receptor activation or inhibition thereof was assessed as [3H]inositol phosphate (IP) accumulation. Quinazoline (alfuzosin, doxazosin, prazosin, terazosin) and non-quinazoline α1-adrenoceptor antagonists (BE 2254, SB 216,469, tamsulosin) concentration-dependently inhibited phenylephrine-stimulated IP formation at both WT and CAM with K i values similar to those previously found in radioligand binding studies. At CAM in the absence of phenylephrine, the quinazolines produced concentration-dependent inhibition of basal IP formation; the maximum inhibition was ~55%, and the corresponding EC50 values were slightly smaller than the K i values. In contrast, BE 2254 produced much less inhibition of basal IP formation, SB 216,469 was close to being a neutral antagonist, and tamsulosin even weakly stimulated IP formation. The inhibitory effects of the quinazolines and BE 2254 as well as the stimulatory effect of tamsulosin were equally blocked by SB 216,469 at CAM. At WT in the absence of phenylephrine, tamsulosin did not cause significant stimulation and none of the other compounds caused significant inhibition of basal IP formation. We conclude that α1-adrenoceptor antagonsits with a quinazoline structure exhibit greater efficacy as inverse agonists than those without.

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Hein, P., Goepel, M., Cotecchia, S. et al. A quantitative analysis of antagonism and inverse agonism at wild-type and constitutively active hamster α1B-adrenoceptors. Naunyn-Schmied Arch Pharmacol 363, 34–39 (2001). https://doi.org/10.1007/s002100000329

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  • DOI: https://doi.org/10.1007/s002100000329

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