Current Medicinal Chemistry, 2006, 13, 3609-3625 3609 Potent Adenosine A 1 and A 2A Receptors Antagonists: Recent Developments O. Yuzlenko and K. Kiec-Kononowicz * ´ Department of Technology and Biotechnology of Drugs, Medical College, Jagiellonian University, Medyczna 9, 30-688 Kraków, Poland Abstract : This review summarizes the current tendencies observed in the past 5 years in the development of A 1 and A 2A adenosine receptor antagonists performed in various academia and industry. A 1 and A 2A AR antagonists are as well xanthines as heteroaromatic derivatives and are most commonly 6:5 fused heteroatomic compounds. Among xanthine-based compounds, some common features could be pointed out. The recent A 1 AR ligands which show good biological profile, possess long alkyl chains in position 1 and 3 as well as bulky C(8)- substituent, while A 2A AR antagonists with a high A 2A AR affinity are C(8)-styryl substituted with N(1)- alkyl/alkynyl moiety or fused tricyclic xanthines possessing heteroatom(s) in the third cycle. The research in the field of heteroaromatic A 1 and A 2A ARs antagonists impressively has a wide range. Ligands are as well non-fused monocyclic substituted compounds as fused bi- and tricyclic derivatives with the nitrogen, oxygen and sulfur heteroatoms. Most often, adenosine A 1 receptor non-xanthine antagonists are adenine-based, having substituted amino group and variable nitrogen atoms positions in the molecules. A 2A AR ligands show good affinity when furanyl function, which is crucial for binding, is present in the fused bicyclic and tricyclic analogs. Moreover, tricyclic nitrogen containing antagonists in order to be active, frequently possess long-alkylphenyl moiety. Keywords: A 1 Adenosine receptor antagonists, A 2A Adenosine receptor antagonists, Xanthine derivatives, Nitrogen (poly)heterocyclic compounds. INTRODUCTION protein, either active by an energy requiring nucleoside transporter protein capable of concentrative transport. Enzymatic-elimination upon deamination by adenosine deaminase to inosine is also possible. Intracellular adenosine is either metabolized enzymatically by adenosine deaminase to inosine; or by adenosine kinase, forming 5’-AMP. The adenosine kinase pathway is preferred at low adenosine concentration, whereas adenosine deaminase when adenosine concentration is high [5]. Adenosine, a major constituent of nucleic acids, that consists of the purine base adenine linked to the ribose moiety, has important and diverse effects on many biological processes. Some of the physiological actions of adenosine include effects on heart rate and atrial contractility, vascular smooth muscle tone, release of neurotransmitters, lipolysis, renal function and white blood cell functions [1, 2]. Adenosine Receptors Classification Through ATP, ADP and AMP, adenosine is directly linked to the energy metabolism of cells (Fig. (1)). The main pathway for adenosine formation starts from AMP, and is catalyzed by enzyme endo-5’-nucleotidase intracellularly and ecto-5’-nucleotidase extracellularly [3, 4]. The other way of adenosine biosynthesis is the intracellular enzymatic conversion of S-adenosylhomocysteine to adenosine. The ability of the extracellular adenosine to regulate metabolism has been intensively studied since the original description of the cardiovascular effects of adenosine administration was made. Subsequent studies over the next four decades uncovered a vast array of effects of purinergic compounds on many different cell types and prompted the adoption of what is presently the basis of the currently accepted nomenclature for purine and pyrimidine receptors [1, 2, 6]. Purine and pyrimidine receptors were classified in accordance with their preference for binding either nucleoside adenosine (P1 receptor subtypes) or P2 receptors recognizing primarily purine nucleotides ATP, ADP and pyrimidine nucleotides UTP and UDP. Based on the differences in molecular structure and signal transduction mechanisms, P2 receptors are divided into two families of ligand-gated ion channels and G protein-coupled receptors termed P2X and P2Y receptors. P1 receptors have been further subdivided according to convergent molecular (cloning and characterization from several mammalian species [3, 7-9]), biochemical and pharmacological evidences into four subtypes A 1 , A 2A , A 2B and A 3 all of which couple to G Transport of intracellularly produced adenosine out of the cell, where the extracellular part of adenosine receptors is located, is primarily maintained by facilitated diffusion through a specific nucleoside transporter protein. The lifetime of adenosine in circulation is in the order of several seconds. This rapid degradation means that adenosine acts locally, close to the sites where it first enters circulation. The elimination of extracellular adenosine occurs most commonly by diffusion back into the cell that may be facilitated by a specific-equilibrative nucleoside transporter *Address correspondence to this author at the Department of Technology and Biotechnology of Drugs, Medical College, Jagiellonian University; Medyczna 9; 30-688 Kraków; Poland; Tel/Fax: +48 12 657 04 88; E-mail: mfkonono@cyf-kr.edu.pl 0929-8673/06 $50.00+.00 © 2006 Bentham Science Publishers Ltd.