History and nomenclature of α1-adrenoceptors

Until 1974 it was widely accepted that alpha-adrenoceptors represented a homogeneous population of receptors. Following the discovery of presynaptic, release-modulating receptors and based on differences in potency for the alpha-adrenoceptor antagonist phenoxybenzamine, it was proposed in 1974 that alpha-adrenoceptors should be subdivided in alpha(1)- and alpha(2)-subtypes. The concept of subtypes of the alpha(1)-adrenoceptor was first suggested in the mid '1980s on the basis of the different affiniries for the agonist, oxymetazoline, and the antagonists, WB4101 and phentolaminson certain alpha(1)-adrenoceptor mediated pharmacological preparations. Subsequent characterization of the alpha(1)-adrenoceptor using radioligand binding and functional studies has led to the identification of three native prazosin-high-affinity alpha(1)-adrenoceptor subtypes designated alpha(1)A, alpha(1B), and alpha(1D), corresponding to the three alpha(1)-adrenoceptor subtypes (alpha(1a), alpha(1b), and alpha(1d)) characterized by molecular cloning techniclues. Studies concerning the distributionn of al-adrenocsptors in the human prostate tissue have shown that the predominant cloned alpha(1a)-adrenoceptor subtype characterized by RNAase protection assays corresponds to the alpha(1a)-subtype. Both obstruction and lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) are enhanced by noradrenergic activation of stromal alpha(1)-adrenoceptors in the enlarged prostate. Therefore, the prostatic alpha(1)-adrenoceptors have become an important target for the pharmacatherapeutic treatment of BPH. In this context, Alfuzosin was the first uroselective alpha(1)-adrenoceptor antagonist to be evaluated in the treatment of BPH and was subsequently marketed, initially in France, in 1987. This drug has since become the standard alpha(1)-adrenoceptor blocker in the treatment of BPH and is widely marketed in Europe. Many of the alpha(1)-adrenoceptor antagonists currently prescribed in the treatment of BPH do not exhibit in vitro selectivity between alpha(1A), alpha(1B), and alpha(1D)-subtypes and yet they have good clinical tolerance in terms of low incidence of cardiovascular effects. One possibility to explain these findings is that another alpha(1)-adrenoceptor subtype could be implicated in human prostatic smooth muscle contraction. There is some evidence that an alpha(1)-adrenoceptor subtype with lower affinity for prazosin designed alpha(1L), which has not been cloned yet, may be the predominant alpha(1)-subtype involved in the contractile response of the human prostatic smooth muscle to noradrenaline.