Current Topics in Medicinal Chemistry - Volume 10, Issue 10, 2010

Adenosine is an endogenous purine nucleoside distributed in several tissues in mammalian organisms where it plays a key role in a large variety of physiological processes. Under normal conditions, adenosine is formed intracellularly and extracellularly. The intracellular production of adenosine is mainly derived from the dephosphorylation of AMP via a cytosolic 5'-nucleotidase, whereas the extracellular production of adenosine is mainly derived from the action of ecto-5'-nucleotidases that mediate the dephosphorylation of AMP derived from the metabolism of extracellular adenine nucleotides Currently, four adenosine receptor subtypes (A1, A2A, A2B, and A3) have been cloned and characterized in several species including rat, mouse, and human. These receptors belong to the rhodopsin-like family of G-protein-coupled receptors (GPCRs), and are encoded by distinct genes. The stimulation of adenosine receptors activates several effector systems, such as the enzyme adenylyl cyclase. A1 and A3 subtypes mainly signal via Gi proteins mediating the inhibition of adenylyl cyclase, whereas the A2A andA2B subtypes mainly signal via the Gs proteins, causing the activation of adenylyl cyclase and thus stimulating the formation of cAMP. Moreover, adenosine can also modulate additional effector systems, including potassium or calcium channels and phospholipases. Several experiments have provided insights into the physiology and pathophysiology of the four adenosine receptor subtypes. The activation of A1AR may be useful in protecting the heart and other tissues from ischemia. A1AR selective antagonists have a therapeutic potential in the treatment of various forms of dementia, such as Alzheimer's disease and depression. Activation of A2AAR is potentially useful for the treatment of cardiovascular diseases, such as hypertension, ischemic cardiomyopathy, inflammation, and atherosclerosis. A2AAR antagonists have been proposed as novel therapeutics for neurodegenerative diseases such as Parkinson's disease and epilepsy disorder. A2BAR agonists are therapeutically promising for their involvement in ischemic preconditioning and A2BAR antagonists have been reported for their activity in asthma and colonic inflammation. Finally, the A3AR agonists have cardioprotective and cerebroprotective effects as well as cytostatic properties, whereas A3AR antagonists could be used as potential drugs for the treatment of asthma and inflammatory conditions. Due to all these possible therapeutical applications, efforts have been carried out by industries and academicians in obtaining selective agonists, antagonists and allosteric enhancers for these four receptor subtypes. As a result, more than 20 clinical trials are currently ongoing and on April 10, 2008, CV Therapeutics, Inc. received approval from the US Food and Drug Administration (FDA) for the use of Lexiscan® (regadenoson; CVT-3146) as a pharmacological stress agent in conjunction with radionuclide MPI. This event can be considered the end point of about thirty years of studies on adenosine receptor ligands but also a new starting point for increasing the interest surrounding adenosine ligands. Two consecutives issues of Current Topics in Medicinal Chemistry highlight the most important aspects of research relating to adenosine. This second issue begins with the article by Taliani and co-workers which summarizes the most recent developments made in the field of selective A3 receptor ligands, pointing the attention on their main chemical structural features and on the SARs, which determine ligand affinity and selectivity for the target subtype. La Motta and co-workers updates the literature on allosteric modulators that has appeared in the last few years, focusing the attention on medicinal chemistry, in terms of chemical structure and SARs. Botta and co-workers and Dal Ben and co-workers report a computational analysis in terms of receptor and ligand-based studies and in the last article, Giordano and co-workers highlight the mouse animal models that have been useful in designing new selective adenosine ligands as well as discuss the main adenosine receptor ligands in clinical trials. As guest editors, we would like to thank the contributing authors for their efforts and, on behalf of all co-authors, we would like to express gratitude to Dr Allen Reitz, Editor-in-Chief of Current Topics in Medicinal Chemistry.

The A3 adenosine receptors (A3 ARs), belonging to the adenosine receptor family of G-protein-coupled receptors (GPCRs), are ubiquitously expressed in a wide variety of tissues in human body, with high levels in peripheral organs and low levels in the brain. The A3 ARs are involved in a variety of important patho-physiological processes, including modulation of cerebral and cardiac ischemic damage, inflammation, modulation of intraocular pressure, regulation of normal and tumor cell growth, and immunosuppression. Consequently, A3 AR selective ligands may represent important pharmacological tools in the treatment of a variety of diseases. Indeed, the development of potent and selective A3 AR ligands has been the subject of medicinal chemistry research for more than two decades. Although to date a considerable number of selective A3 AR agonists and antagonists have been discovered, much is still to be learned about the exact function of this subtype, due to its enigmatic role in several physiological processes. In the last two decades, numerous medicinal chemistry groups have made intense efforts in searching for ideal ligands for the A3 AR subtype. The purpose of this review is to summarize the most recent developments made in the field of selective A3 AR ligands, which have been subdivided on the basis of their main chemical structural features. For each chemical class, attention has been focused on the SARs which determine ligand affinity and selectivity for the target subtype, and on eventually available preclinical data.

Adenosine is a ubiquitous homeostatic substance which exerts its action by triggering four different cell membrane G protein-coupled receptors, classified as A1, A2A, A2B, and A3. As they are widely distributed and deeply involved in several physiological functions, as well as pathological disorders, these receptors represent an excellent drug target, and the development of specific ligands has been tested as a promising therapeutic concept. Among the obtainable ligands, allosteric modulators offer higher advantages with respect to classical orthosteric compounds, as they make it possible to achieve greater selectivity and better modulatory control at disease mediating receptors. Actually, when synergizing with adenosine bound to the primary binding site, these compounds may modify receptor functions through interaction with an additional binding site. As a consequence, their actions depend directly on the release of the endogenous agonist. A number of compounds have been developed as effective allosteric modulators. Most of them target adenosine A1 and A3 receptor subtypes whereas, to date, little or no research has been made to improve the field of A2A or A2B ligands. This review updates literature on the allosteric modulators that has appeared in the last few years, focusing its attention on medicinal chemistry, in terms of chemical structure and structure-activity relationships. This will provide new perspectives on existing data, and an exciting starting point for the development of novel and more effective modulators.

For a long time, there have been no experimentally determined structural data for any adenosine receptor (AR) and the only approach available for making structure/function correlations about these proteins has been homology modeling. While the early attempts to model these receptors followed the crystallization of bacteriorhodopsin, the cryomicroscopy studies of bovine and frog rhodopsin, and the modeling of a Cα-template for the TM helices in the rhodopsin family of GPCRs, the crystallization of bovine rhodopsin by Palczewski was of extreme importance as it first provided the crystal structure of an eukaryotic GPCR to be used as template for more realistic homology models. Since then, rhodopsin-based modeling became the routine approach to develop AR structural models that proved to be useful for interpretation of site-directed mutagenesis data and for molecular docking studies. The recently reported crystal structures of the adrenergic beta1 and beta2 receptors only partially confirmed the structural features showed by bovine rhodopsin, raising a question about which template would have been better for further modeling of ARs. Such question remained actually not-answered, due to the publication in late 2008 of the crystal structure of human adenosine A2A receptor (AA2AR). Since its publication, this structure has been used for ligands docking analysis and has provided a high similarity template for homology modeling of the other AR subtypes. Still, the AA2AR crystal structure allows to verify the hypotheses that were made on the basis of the previously reported homology modeling and molecular docking.

Computational methodologies are used to increase the efficiency of drug discovery process by rendering the design of new drug candidates more rapid and cost-efficient. In silico techniques can be divided in two main groups. Structure-based drug design procedures can be applied (such as docking simulations) if the target is known from experimental (i.e., X-ray crystallographic studies, NMR studies) or theoretical sources (receptor structure built by homology modeling techniques). Otherwise, ligand-based drug design methods can be used (e.g., QSAR or 3D QSAR models, pharmacophoric models) based on the analysis of a number of ligands known to act with a common mechanism of action. Adenosine receptors (ARs) are a family of G-protein coupled receptors (GPCRs) of great interest as targets for therapeutic intervention. Due partly to the lack of reliable adenosine receptor structures, ligand-based drug discovery methods remain the major computational molecular modeling approach applied in the research of new AR ligands. The scope of this review is to summarize the results on pharmacophoric models and 3D QSAR studies concerning AR ligands. In particular, the review will focus on the use of such ligand-based computational techniques for the identification of new AR ligands and/or for their optimization.

Adenosine and its receptors play different roles in normal and patho-physiological conditions. For these reasons, many laboratories have focused their attention on dissecting the molecular pathway underlying the mechanism of action of this nucleoside with the final goal being to design new drugs. Wide expression and overlapping functions have been the major problems to designing specific adenosine agonists and antagonists with few associated negative side effects. Engineered mice have helped to dissect the single adenosine receptor function in specific tissues and pathological conditions. All these efforts in the last 20 years have led to the design of more than 2000 compounds, some of them now in clinical trials for treating different pathologies. In this review, we highlight the mouse animal models that have been of use in designing new selective drugs as well as discuss the main adenosine receptor ligands in clinical trials.