Editorial [Hot Topic: Adrenoceptors as Targets in Drug Discovery: Medicinal Chemistry and Therapeutical Potential (Guest Editors: Professors Maria Pigini and Wilma Quaglia)]

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.