A Concise and Useful Guide to Understand How Alpha1 Adrenoceptor Antagonists Work

Adrenoceptors are the receptors for catecholamines, adrenaline, and noradrenaline. They are divided in alpha (alpha(1) and alpha(2)) and beta (beta(1), beta(2) and beta(3)). alpha(1)-adrenoceptors are subdivided in alpha(1A), alpha(1B) and alpha(1D). Most tissues express mixtures of alpha(1)-adrenoceptors subtypes, which appear to coexist in different densities and ratios, and in most cases, their responses are probably due to the activation of more than one type. The three subtypes of alpha(1)-adrenoceptors are G-protein-coupled receptors (GPCR), specifically coupled to G(q/11). Additionally, the activation of these receptors may activate other signaling pathways or different components of these pathways, which leads to a great variety of possible cellular effects. The first clinically used alpha(1) antagonist was Prazosin for Systemic Arterial Hypertension (SAH). It was followed by its congeners, Terazosin and Doxazosin. Nowadays, there are many classes of alpha-adrenergic antagonists with different selectivity profiles. In addition to SAH, the alpha(1)-adrenoceptors are used to treat Benign Prostatic Hyperplasia (BPH) and urolithiasis. This antagonism may be part of the mechanism of action of tricyclic antidepressants. Moreover, the activation of these receptors may lead to adverse effects such as orthostatic hypotension, similar to what happens with antidepressants and with some antipsychotics. Structure-activity relationships can explain, in part, how antagonists work and how selective they can be for each one of the subtypes. However, it is necessary to develop new molecules which antagonize the alpha(1)-adrenoceptors or make chemical modifications in these molecules to improve the selectivity and pharmacokinetic profile and/or reduce the adverse effects of known drugs.