%0 Journal Article
%T Pyrazolo Derivatives as Potent Adenosine Receptor Antagonists: An Overview on the Structure-Activity Relationships
%A Siew Lee Cheong
%A Gopalakrishnan Venkatesan
%A Priyankar Paira
%A Ramasamy Jothibasu
%A Alexander Laurence Mandel
%A Stephanie Federico
%A Giampiero Spalluto
%A Giorgia Pastorin
%J International Journal of Medicinal Chemistry
%D 2011
%I Hindawi Publishing Corporation
%R 10.1155/2011/480652
%X In the past few decades, medicinal chemistry research towards potent and selective antagonists of human adenosine receptors (namely, A1, A2A, A2B, and A3) has been evolving rapidly. These antagonists are deemed therapeutically beneficial in several pathological conditions including neurological and renal disorders, cancer, inflammation, and glaucoma. Up to this point, many classes of compounds have been successfully synthesized and identified as potent human adenosine receptor antagonists. In this paper, an overview of the structure-activity relationship (SAR) profiles of promising nonxanthine pyrazolo derivatives is reported and discussed. We have emphasized the SAR for some representative structures such as pyrazolo-[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidines; pyrazolo-[3,4-c] or -[4,3-c]quinolines; pyrazolo-[4,3-d]pyrimidinones; pyrazolo-[3,4-d]pyrimidines and pyrazolo-[1,5-a]pyridines. This overview not only clarifies the structural requirements deemed essential for affinity towards individual adenosine receptor subtypes, but it also sheds light on the rational design and optimization of existing structural templates to allow us to conceive new, more potent adenosine receptor antagonists. 1. Introduction Adenosine is an endogenous nucleoside that mediates a wide range of physiological responses through interaction with specific adenosine receptors (ARs), which are G-protein-coupled receptors (GPCRs) comprising the characteristic seven transmembrane domains connected by three extracellular and three intracellular loops. There are four basic types of ARs that have been cloned and pharmacologically characterized, namely, A1, A2A, A2B, and A3 ARs [1]. Each of these ARs is associated with its own distinct biochemical pathways. Typically, the activation of A1 and A3 receptors mediates adenylyl cyclase inhibition through an interaction with Gi protein, followed by a subsequent decrease in the level of cyclic adenosine monophosphate (cAMP); conversely, the A2A and A2B receptors stimulate the adenylyl cyclase activity via the Gs protein thereby increasing the level of cAMP [2]. In addition, other signaling pathways involving phospholipases C and D, and Ca2+ and mitogen-activated protein kinases (MAPK) have also been described [1]. Pharmacologically, the inhibition of A1 receptors has led to implications in the renal system disorders through regulation of diuresis and neurological disorders such as Alzheimer¡¯s disease [3, 4]; on the other hand, A3 receptor antagonists are primarily related to the treatment of glaucoma, renal protection, inflammatory disorders
%U http://www.hindawi.com/journals/ijmc/2011/480652/