Current Topics in Medicinal Chemistry - Volume 7, Issue 2, 2007

Adrenoceptors continue to represent important and innovative pharmacological targets, even though their discovery dates back to more than 100 years ago: in fact, in 1905 Langley postulated that adrenaline exerted its action by interacting with “receptive substances” [Langley, J. N. J. Physiol. (London) 1905, 33, 374-413]; since then numerous studies have been carried out. The first distinction between α and β receptors was postulated in 1948 by Ahlquist, who, however, in 1973 still had doubts on their effective existence, such a differentiation being defined “...an abstract concept conceived to explain observed responses of tissues produced by chemicals of various structure” [Ahlquist, R. P. Adrenergic Receptors: a Personal and Practical View. Perspect. Biol. Med. 1973, 17, 119-122]. Since then, radioligand binding studies, second messenger assays and molecular biology techniques have led to the identification of nine different subtypes, which, however, do not seem to explain fully all the experimental observations. Even if it is difficult to postulate the existence of other members of this superfamily (however, at the same time most attention has been devoted to two possible candidates, the α1L and β4), the improvement in the selectivity of interaction and, therefore, in the quality of response is explained through the recognition of different affinity states or non-canonical receptor sites. In this issue, after a review of the subclassification of the α- and β-adrenoceptors by Hieble, the recent advances in the discovery of α1-agonists and antagonists are highlighted by Bishop and Melchiorre et al., respectively. Agonists and antagonists directed to α2-adrenoceptors and their clinical utility are described by Giannella et al. and Crassous et al., respectively. Carrieri and Fano examine the methodological approaches and structural features of the 3D models in α- adrenoceptor characterization, and Hieble gives an overview of β-adrenoceptor ligands and their therapeutic uses. Finally, Schaak et al. focus on possible genetic variations of human adrenoceptors. The therapeutic applications of adrenergic ligands are various: for example, the primary indications of the α 1-agonists are in nasal congestion, otitis and in stress urinary incontinence; agonists, acting at the α2-adrenoceptors, are extremely valuable adjuncts to anesthetics and analgesics; those at the β2-adrenoceptors are used as bronchodilators, whereas β3-agonists prove to be efficacious in the treatment of overactive bladder. The use of the β1/β2-antagonists as antihypertensives, α1-antagonists in the treatment of benign prostatic hyperplasia, and α2-antagonists in attention deficit hyperactivity disorder is well established. A better knowledge of the structural differences of the various receptor species, in particular within each of the three distinct classes, and of the possible aggregation of such proteins in homo- and heterodimer forms will help to design new ligands that, being more selective, will have new and safer therapeutic uses.

The subclassification of α- and β-adrenoceptors has resulted in many opportunities for drug discovery. Important adrenoceptor targets include β2-agonists as bronchodilators, β1 or β1/β2 antagonists as antihypertensives, centrally acting α2-agonists for a variety of applications and α1-antagonists for hypertension and benign prostatic hyperplasia. The pharmacology and nomenclature of 9 adrenoceptors is now established, with α1, α2 and β-adrenoceptors being divided into three subtypes each. It is unlikely that additional discrete adrenoceptor sequences will be identified; however the presence of “affinity states” can give rise to tissue specific differences in pharmacology for a specific subtype. Polymorphisms and splice variants of adrenoceptors continue to be identified; in some cases these modifications can affect pharmacological characteristics and could influence the efficacy of adrenoceptor-targeted therapy. Selective antagonists are now available of all 9 adrenoceptor subtypes. Although these will not all have therapeutic application, the availability of improved pharmacologic tools could lead to the identification of new adrenoceptor targets.

The α1 adrenoceptors are three of nine well-characterized receptors that are activated by epinephrine and norepinephrine. Agonists acting at the α1 adrenoceptors produce numerous physiological effects, and are used therapeutically for several indications. Many known α1 adrenoceptor agonists are α1A selective, but the discovery of highly selective α1B and α1D adrenoceptor agonists has proven to be an extremely difficult goal to achieve. This review will focus on recent advances in the discovery, development and clinical utility of subtype-specific α1 agonists as well as contributions to our understanding of agonist-receptor interactions.

Native α1-adrenoreceptors (ARs) appear to exist as three different subtypes encoded by three genes, α1A/1a, α1B/1b, and α1D/1d. Historically, the discovery of agents selective for each of the three α1-AR subtypes has been an active area of medicinal chemistry research because of the wide number of possible therapeutic applications. Initially introduced for the management of hypertension, α1-AR antagonists have, in fact, become increasingly common in the treatment of benign prostatic hyperplasia (BPH), and are effective therapeutic tools, when characterized by an appropriate uroselective profile. The majority of these derivatives display a competitive mechanism of action and belong to a variety of structural classes, but this review is focused on compounds belonging to the quinazoline, benzodioxane, arylpiperazine, and 1,4- dihydropyridine classes.

Chemical and biological strategies have provided evidence for α2-receptor heterogeneity, to date classified in three different subtypes, α2A, α2B, and α2C. These are widely distributed throughout the body and mediate numerous effects; therefore, the potential therapeutic indications of agonists and antagonists are numerous. Nevertheless, the lack of subtype-selectivity of the well-known compounds represents a major limit for their use. SAR studies may help to design new and more selective drugs.

The family of α2-adrenergic receptors (α2-ARs) comprises three subtypes which are each endowed with specific functions. α2-agonists and α2-antagonists are part of the clinician armamentarium since several decades; however, none of the compounds so far available is subtype selective. For long, clonidine and yohimbine have been used for the treatment of hypertension and impotence respectively, but both have been superseded by newer drugs. This review attempts, by a comprehensive analysis of the literature, to cover the present clinical use and the potential therapeutic interest of α2-agonists or antagonists. From the clinical data, it is concluded that, with the exception of a few particular situations, α2-agonists are only of limited utility as a monotherapy. By contrast, they offer several powerful advantages when used in adjunctive therapy. In perioperative settings, α2-agonists are extremely valuable adjuncts to anesthetics and analgesics for the induction of anxiolysis, maintenance of sedation, management of pain and prevention of shivering. In the ophthalmic clinic, they are used to lower intra-ocular pressure during laser surgery of the eye. As a daily medication, α2-agonists are also of interest for the treatment of glaucoma, muscle spasticity, opiate withdrawal, and behavior disorders. The a2-antagonists are useful antidotes for reversing the threatening effects of agonist overdose, but currently there are very few indications. New applications are under investigation, and new molecules with more refined subtypeselectivity may emerge, so the clinical utility of both α2-agonists and antagonists will undoubtedly expand in the future.

Homology modeling has been widely used in the latest years in order to overcome the lackness of adequate structural information. This technique has also been successfully applied in the very difficult but challenging field of Gprotein coupled receptors where the need of three-dimensional insight is significantly more essential. Here we will review the latest advancements in this topic taking as case studies α-adrenergic receptors theoretical models and their structural features.

The three β-adrenoceptor subtypes (β1, β2, β3) represent important therapeutic targets. The use of β2- adrenoceptor agonists as bronchodilators and β1 or β1/β2 antagonists as antihypertensives is well established; research is ongoing in these areas to refine pharmacodynamic properties. It is also feasible to design molecules combining β-adrenoceptor affinity with other pharmacophores. This is facilitated by the ability to confer β- adrenoceptor antagonist activity via attachment of a phenylethanolamine moiety or to incorporate diverse structural elements in the N-alkyl substituent of a β-adrenoceptor agonist or antagonist. β3-Adrenoceptor agonists have not yet been successfully developed as drugs for any therapeutic indication; nevertheless, during the past few years many highly potent and selective β3-agonists have been reported, some with good oral bioavailability. Selective β3-adrenoceptor antagonists have also been identified; useful pharmacological tools are now available for the evaluation of the functional role of each β-adrenoceptor subtype.

Adrenergic receptors (ARs) are directly or indirectly involved in the control of a large panel of physiological functions and are the targets of drugs for the treatment of several common diseases including congestive heart failure, asthma or benign prostatic hyperplasia. The genotyping of human populations with diverse ethnicity has revealed that the genes encoding α1A-, α1B-, α2A-, α2B-, α2C-, β1-, β2- and β3-AR are polymorphic in their coding region as well as in their regulatory domains and non-coding regions. The functional consequences of these genetic variations include changes in expression at transcriptional or translational level, modification of coupling to heterotrimeric G-proteins resulting in a gain or a loss in function, and alteration of GRK-mediated receptor phosphorylation/desensitization or of agonist-promoted down-regulation. None of the mutations identified so far is per se a major risk factor for acquired or inherited disease; however, variants of α2C-AR and β1-AR may act in synergy to determine the progression of heart failure and certain combinations of polymorphisms on β2-AR correlate with asthmatic phenotypes or response to β2-agonist therapy. Herein we summarize the present knowledge on AR gene polymorphisms, and discuss the putative consequences of variations resulting in receptor malfunction on pharmacogenomics and disease predisposition.