Preclinical Pharmacology of α1-Adrenoceptor Antagonists

Abstract

The implication of a single adrenoceptor subtype in the contractility of prostatic and urethral smooth muscle cells led to the concept that drugs with selectivity for this subtype may exhibit functional uroselectivity. Comparison of the affinities of the α₁-adrenoceptor antagonists revealed that few compounds show selectivity for one of the three cloned α₁-adrenoceptor subtypes (α_1a/A, α_1b/B, α_1d/D) whereas most of them had a similar affinity for the three subtypes. Moreover, data supporting a relationship between selectivity for the α_1a/A-adrenoceptor subtype and functional uroselectivity are still lacking and recent data challenged the relevance of the selectivity for a given cloned α₁-adrenoceptor subtype in predicting functional uroselectivity. In vivo data showed that α₁-adrenoceptor antagonists without adrenoceptor subtype selectivity, like alfuzosin or to a minor extent doxazosin, showed functional uroselectivity whereas prazosin and terazosin were not shown to be uroselective. Compounds considered to be selective for the α_1a/A-adrenoceptor, like tamsulosin or 5-Me-urapidil, did not show functional uroselectivity since they modified urethral and blood pressures in a manner which was not correlated to their selectivity for the cloned α₁-adrenoceptor subtypes. Meanwhile, the identification in prostatic tissue, of a new sub-family of α₁-adrenoceptors with low affinity for prazosin and denominated α_1L gave rise to numerous studies. However, its functional role as well as the affinity of the known antagonists for this receptor subtype remains to be clarified. In conclusion, the existing α₁-adrenoceptor antagonists have different pharmacological profiles in vivo which are yet not predictable from their receptor pharmacology based on the actual state of knowledge of the α₁-adrenoceptor classification.