Recent advances in the identification of a 1- and a 2-adrenoceptor subtypes: therapeutic implications

Abstract

The cloning of multiple subtypes of both a1- and a2-adrenoceptors has renewed interest in the therapeutic application of agents interacting with these receptors. Effort has primarily been directed towards the design of uroselective a1-adrenoceptor antagonists for the treatment of benign prostatic hyperplasia (BPH). Evidence is accumulating for the involvement of a novel a1-adrenoceptor, designated as a1L-adrenoceptor, in a1-adrenoceptor-mediated smooth muscle contraction in prostatic and other urogenital tissues. While several antagonists showing a high degree of uroselectivity in animal models have been identified, their clinical superiority over the currently available a1-adrenoceptor antagonists has not yet been demonstrated. It is possible that the interaction with a1-adrenoceptors, as yet uncharacterised subtypes, at non-prostatic sites contributes to the therapeutic activity of this drug class in BPH. The a1-adrenoceptor subtypes involved in the control of vascular tone are currently being evaluated, and the profile of interaction with the various a1-adrenoceptor subtypes may play a key role in the efficacy of cardiovascular drugs such as carvedilol. a2-Adrenoceptor agonists are now being employed for a variety of therapeutic applications, most involving actions on receptors within the central nervous system (CNS). These agents are useful in the treatment of hypertension, glaucoma, opiate withdrawal and attention deficit hyperactivity disorder (ADHD), and as analgesics and adjuncts to general anaesthesia. While subtype selectivity has not yet been applied to the design of new a2-adrenoceptor agonists for these applications, recent gene mutation/knock-out experiments have identified the a2-subtypes involved in some of these actions, and optimisation of a therapeutic profile may be possible. Furthermore, the design of agents combining affinities for multiple adrenoceptor subtypes, or the combination of a specific adrenoceptor affinity profile with another pharmacological action, may offer advantages over molecules selective for an individual adrenoceptor subtype

• 1-adrenoceptor
• 2-adrenoceptor
• 1L-adrenoceptor
• benign prostatic hyperplasia
• hypertension
• vascular tone