Adrenoceptor subclassification: an approach to improved cardiovascular therapeutics

The subdivision of alpha adrenoceptors into the alpha 1 and alpha 2 classes was the impetus for the design of the selective alpha 1-adrenoceptor antagonists, which remain useful antihypertensives. alpha 2-Adrenoceptor agonists also have application as antihypertensive drugs, based on their ability to reduce sympathetic outflow. Likewise, subdivision of the beta adrenoceptors has lead to the development of selective beta 1-adrenoceptor antagonists as antihypertensive and selective beta 2 agonists as bronchodilators. In the past decade, both the alpha 1 and alpha 2 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 "alpha 1L" adrenoceptor and "beta 4" adrenoceptor. alpha 1A (or alpha 1L)-Adrenoceptor antagonists have been evaluated for benign prostatic hyperplasia (BPH), and selective alpha 1A agonists for stress incontinence. Gene knockout experiments in mice suggest an important role for the alpha 1B adrenoceptor in the control of vascular tone. Hence, selective alpha 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 alpha/beta-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.