History and nomenclature of alpha1-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 alpha1- and alpha2-subtypes. The concept of subtypes of the alpha1-adrenoceptor was first suggested in the mid 1980s on the basis of the different affinities for the agonist, oxymetazoline, and the antagonists, WB4101 and phentolamine on certain alpha1-adrenoceptor mediated pharmacological preparations. Subsequent characterization of the alpha1-adrenoceptor using radioligand binding and functional studies has led to the identification of three native prazosin-high-affinity alpha1-adrenoceptor subtypes designated alpha1A, alpha1B, and alpha1D, corresponding to the three alpha1-adrenoceptor subtypes (alpha1a, alpha1b, and alpha1d) characterized by molecular cloning techniques. Studies concerning the distribution of alpha1-adrenoceptors in the human prostate tissue have shown that the predominant cloned alpha1a-adrenoceptor subtype characterized by RNAase protection assays corresponds to the alpha1A-subtype. Both obstruction and lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) are enhanced by noradrenergic activation of stromal alpha1-adrenoceptors in the enlarged prostate. Therefore, the prostatic alpha1-adrenoceptors have become an important target for the pharmacotherapeutic treatment of BPH. In this context, Alfuzosin was the first uroselective alpha1-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 alpha1-adrenoceptor blocker in the treatment of BPH and is widely marketed in Europe. Many of the alpha1-adrenoceptor antagonists currently prescribed in the treatment of BPH do not exhibit in vitro selectivity between alpha1A, alpha1B, and alpha1D-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 alpha1-adrenoceptor subtype could be implicated in human prostatic smooth muscle contraction. There is some evidence that an alpha1-adrenoceptor subtype with lower affinity for prazosin designed alpha1L, which has not been cloned yet, may be the predominant alpha1-subtype involved in the contractile response of the human prostatic smooth muscle to noradrenaline.