Current Topics in Medicinal Chemistry - Volume 10, Issue 9, 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. In this issue, the first article by Trincavelli and co-workers introduces adenosine receptors, and summarize what we know and what we are learning about adenosine receptor structure, signalling and regulatory mechanisms. In the second article, Schenone and co-workers focus on the A1 adenosine receptor ligands together with their potential therapeutic application, pointing the attention on their chemical structures and SAR and also reporting new findings on preclinical or clinical trials of some important A1 receptor ligands synthesized in the past. Using the same plan, in the following two articles Manera and co-workers and Martinelli and co-workers analyze the A2A and A2B receptor ligands, respectively.

Adenosine, beside its role in the intermediate metabolism, mediates its physiological functions by interacting with four receptor subtypes named A1, A2A, A2B and A3. All these receptors belong to the superfamily of G protein-coupled receptors that represent the most widely targeted pharmacological protein class. Since adenosine receptors are widespread throughout the body, they are involved in a variety of physiological processes and pathology including neurological, cardiovascular, inflammatory diseases and cancer. At now, it is ascertained that the biological responses evoked by the activation of a single receptor are the result of complex and integrated signalling pathways targeted by different receptor proteins, interacting each other. These pathways may in turn control receptor responsiveness over time through fine regulatory mechanisms including desensitization-internalization processes. The knowledge of adenosine receptor structure as well as the molecular mechanisms underlying the regulation of receptor functioning and of receptor-receptor interactions during physiology and pathological conditions represent a pivotal starting point to the development of new drugs with high efficacy and selectivity for each adenosine receptor subtype. The goal of this review is to summarize what we now and what we are learning about adenosine receptor structure, signalling and regulatory mechanisms. In addition, to dissect the potential therapeutic application of adenosine receptor ligands, the pathophysiological role of the receptor subtypes in different tissues is discussed.

Adenosine is a neuromodulator that interacting with four receptors, A1, A2A, A2B and A3, is involved in the regulation of several biological functions in different organs and tissues, including the central nervous system, the cardiovascular system and the airways; many pathophysiological states are associated with changes of adenosine levels. For these reasons pharmaceutical companies and academicians performed intense efforts to obtain agonists, antagonists and allosteric enhancers selective for each adenosine receptor subtypes as potential clinical candidates. In fact, therapeutic modulation of the adenosine system could offer the possibility of a “soft” treatment of different diseases, but, due to the ubiquitous distribution of adenosine and of its receptors, the challenge in therapy development depends from specificity for the different receptor subtypes. Some A1 agonists and antagonists, very potent and selective, reached clinical trials for the treatment of different diseases. A1 agonists are clinical candidates for atrial arrhythmias, angina, type 2 diabetes and in pain management, while A1 antagonists are in study as potassium-sparing diuretics with kidney-protecting properties and in chronic heart diseases. Several reviews, recently published and herein cited, reported in detail the biological and clinical aspects of such molecules. This review focuses on the A1 adenosine receptor (A1AR) ligands, both agonists and antagonists, appeared in the literature in the last few years, together with their potential therapeutic application, pointing the attention on their chemical structures and SAR (Structure Activity Relationship) and also reporting new findings on preclinical or clinical trials of some important A1AR ligands synthesized in the past.

The adenosine A2A receptor is a member of the G protein-coupled receptor family and mediates multiple physiological effects of adenosine, both at the central nervous system and at peripheral tissues. Increasing evidence relates the A2A receptor with several pathological conditions such as neurodegenerative disorders, inflammation, pharmacological stress, and wound healing renewing the interest in A2A receptor agonists and antagonists as promising leads for drugs. However some of them initially tested in clinical trials presented several side effects, short half-life, lower solubility, and in some cases a lack of effects, perhaps attributable to receptor desensitization or to low receptor density in the targeted tissue. For these reasons it is evident that additional rational chemical modifications of the existing A2A receptor ligands to improve their affinity/selectivity and bioavailability as well as further studies to get new template for A2AAR ligands are necessary. The purpose of this review is to analyze and summarize the past and the present aspects related to the medicinal chemistry of A2A receptor ligands. Moreover their current and possible therapeutic applications have been also highlighted

A2B adenosine receptors have been investigated in recent years as potential target for the treatment of different pathologies. The involvement of this receptor in processes such as interleukins secretion, Ca2+ mobilization, hepatic glucose regulation, tumor vascularisation, and cardioprotection have stimulated many researchers to develop specific agonists and antagonists. For many years, the lack of potent and selective A2B ligands precluded a deep exploration of their therapeutic prospective; at present, much progress in the field of antagonists led to preclinical studies for different compounds. Less populated is the universe of A2B agonists, but really promising for the involvement in ischemic preconditioning. A summary of the most significant advancements in the synthesis of new compounds and of the principal structure activity relationships is reported. The xanthine-based A2B antagonists currently show the better profile of affinity and selectivity, as CVT-6883 (CVT-Therapeutics: Ki(A2B)=22 nM, and selectivity higher than 50-fold over other subtypes), MRE-2029-F20 (Baraldi's group: Ki(A2B)=5.5 nM, selectivity >180 fold), LAS38096 (Almirall Prodesfarma: Ki(A2B)=17 nM, selectivity >60 fold), OSIP339391 (OSI Pharmaceuticals: Ki(A2B)=0.5 nM, selectivity >80 fold), PSB601 (Bonn University: Ki(A2B)=3.6 nM, selectivity >140 fold) and the deazaxanthine 32 of Carotti's group (Ki(A2B)=11 nM, selectivity >90 fold). Other recently emerging scaffolds with promising biological profiles are described. With regard to the agonists, many research groups are involved in the discovery of useful agonist radioligands, but the only example of potent and rather selective A2B agonists are compound 65, recently synthesized, and BAY-60-6583, that is under preclinical phase investigation.