Adrenoceptor subclassification: an approach to improved cardiovascular therapeutics

Abstract

The subdivision of α adrenoceptors into the α₁ and α₂ classes was the impetus for the design of the selective α₁-adrenoceptor antagonists, which remain useful antihypertensives. α₂-Adrenoceptor agonists also have application as antihypertensive drugs, based on their ability to reduce sympathetic outflow. Likewise, subdivision of the β adrenoceptors has lead to the development of selective β₁-adrenoceptor antagonists as antihypertensives and selective β₂ agonists as bronchodilators. In the past decade, both the α₁ and α₂ adrenoceptors have been further subdivided, each into three subclasses. In addition, there is strong functional evidence to suggest the presence of additional adrenoceptor subtypes, such as the “α_1L” adrenoceptor and “β₄” adrenoceptor. α_1A (or α_1L)-Adrenoceptor antagonists have been evaluated for benign prostatic hyperplasia (BPH), and selective α_1A agonists for stress incontinence. Gene knockout experiments in mice suggest an important role for the α_1B adrenoceptor in the control of vascular tone. Hence, selective α_1B antagonists may offer a new approach toward hypertension. Although targeting of specific adrenoceptors can be used to optimize the therapeutic profile of a drug, there are also cases where blockade of multiple adrenoceptors is desirable, as with the α/β-adrenoceptor antagonist carvedilol in congestive heart failure. It is possible that combination of affinities for selected adrenoceptor subtypes within a single molecule may be desirable for certain applications.