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
References
[1]
K. A. Jacobson and Z. G. Gao, “Adenosine receptors as therapeutic targets,” Nature Reviews Drug Discovery, vol. 5, no. 3, pp. 247–264, 2006.
[2]
S. Moro, Z. G. Gao, K. A. Jacobson, and G. Spalluto, “Progress in the pursuit of therapeutic adenosine receptor antagonists,” Medicinal Research Reviews, vol. 26, no. 2, pp. 131–159, 2006.
[3]
W. J. Welch, “Adenosine A1 receptor antagonists in the kidney: effects in fluid-retaining disorders,” Current Opinion in Pharmacology, vol. 2, no. 2, pp. 165–170, 2002.
[4]
T. V. Dunwiddie and S. A. Masino, “The role and regulation of adenosine in the central nervous system,” Annual Review of Neuroscience, vol. 24, pp. 31–55, 2001.
[5]
K. A. Jacobson, “Adenosine A3 receptors: novel ligands and paradoxical effects,” Trends in Pharmacological Sciences, vol. 19, no. 5, pp. 184–191, 1998.
[6]
T. Okamura, Y. Kurogi, K. Hashimoto, H. Nishikawa, and Y. Nagao, “Facile synthesis of fused 1,2,4-triazolo[1,5-c]pyrimidine derivatives as human adenosine A3 receptor ligands,” Bioorganic and Medicinal Chemistry Letters, vol. 14, no. 10, pp. 2443–2446, 2004.
[7]
S. Merighi, P. Mirandola, K. Varani et al., “Pyrazolotriazolopyrimidine derivatives sensitize melanoma cells to the chemotherapic drugs: taxol and vindesine,” Biochemical Pharmacology, vol. 66, no. 5, pp. 739–748, 2003.
[8]
R. Grondin, P. J. Bédard, A. H. Tahar, L. Grégoire, A. Mori, and H. Kase, “Antiparkinsonian effect of a new selective adenosine receptor antagonist in MPTP-treated monkeys,” Neurology, vol. 52, no. 8, pp. 1673–1677, 1999.
[9]
P. Jenner, “Istradefylline, a novel adenosine receptor antagonist, for the treatment of Parkinson's disease,” Expert Opinion on Investigational Drugs, vol. 14, no. 6, pp. 729–738, 2005.
[10]
I. Feoktistov, I. Biaggioni, R. Polosa, and S. T. Holgate, “Adenosine receptors: a novel therapeutic target in asthma?” Trends in Pharmacological Sciences, vol. 19, no. 4, pp. 148–153, 1998.
[11]
S. T. Holgate, “The identification of the adenosine receptor as a novel therapeutic target in asthma,” British Journal of Pharmacology, vol. 145, no. 8, pp. 1009–1015, 2005.
[12]
S. Schenone, M. Radi, and M. Botta, “Pyazolopyrimidines: old molecules, new targets,” Targets in Heterocyclic Systems-Chemistry and Properties, vol. 11, pp. 44–69, 2007.
[13]
F. Gatta, M. R. Del Giudice, A. Borioni, P. A. Borea, S. Dionisotti, and E. Ongini, “Synthesis of imidazo[1,2-c]pyrazolo[4,3-e]pyrimidines, pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidines and 1,2,4-triazolo[5,1-i]purines: new potent adenosine A2 receptor antagonists,” European Journal of Medicinal Chemistry, vol. 28, no. 7-8, pp. 569–576, 1993.
[14]
P. G. Baraldi, S. Manfredini, D. Simoni et al., “Sythesis of new pyrazolo[4,3-e]1,2,4-triazolo[1,5-c] pyrimidine and 1,2,3-triazolo[4,5-e]1,2,4-triazolo[1,5-c] pyrimidine displaying potent and selective activity as adenosine receptor antagonists,” Bioorganic and Medicinal Chemistry Letters, vol. 4, no. 21, pp. 2539–2544, 1994.
[15]
P. G. Baraldi, B. Cacciari, G. Spalluto et al., “Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine derivatives: potent and selective adenosine antagonists,” Journal of Medicinal Chemistry, vol. 39, no. 5, pp. 1164–1171, 1996.
[16]
P. G. Baraldi, B. Cacciari, G. Spalluto et al., “Design, synthesis, and biological evaluation of a second generation of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines as potent and selective adenosine receptor antagonists,” Journal of Medicinal Chemistry, vol. 41, no. 12, pp. 2126–2133, 1998.
[17]
P. G. Baraldi, B. Cacciari, R. Romagnoli et al., “7-substituted 5-amino-2-(2-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines as adenosine receptor antagonists: a study on the importance of modifications at the side chain on the activity and solubility,” Journal of Medicinal Chemistry, vol. 45, no. 1, pp. 115–126, 2002.
[18]
S. Dionisotti, S. Ferrara, C. Molta, C. Zocchi, and E. Ongini, “Labeling of adenosine receptors in human platelets by use of the new nonxanthine antagonist radioligand [ 3H]SCH 58261,” Journal of Pharmacology and Experimental Therapeutics, vol. 278, no. 3, pp. 1209–1214, 1996.
[19]
S. Todde, R. M. Moresco, P. Simonelli et al., “Design, radiosynthesis, and biodistribution of a new potent and selective ligand for in vivo imaging of the adenosine receptor system using positron emission tomography,” Journal of Medicinal Chemistry, vol. 43, no. 23, pp. 4359–4362, 2000.
[20]
M. Kecskés, T. S. Kumar, L. Yoo, Z. G. Gao, and K. A. Jacobson, “Novel Alexa Fluor-488 labeled antagonist of the adenosine receptor: application to a fluorescence polarization-based receptor binding assay,” Biochemical Pharmacology, vol. 80, no. 4, pp. 506–511, 2010.
[21]
P. G. Baraldi, B. Cacciari, R. Romagnoli et al., “Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine derivatives as highly potent and selective human A3 adenosine receptor antagonists,” Journal of Medicinal Chemistry, vol. 42, no. 22, pp. 4473–4478, 1999.
[22]
P. G. Baraldi, B. Cacciari, R. Romagnoli et al., “Pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine derivatives as highly potent and selective human A3 adenosine receptor antagonists: influence of the chain at the N8 pyrazole nitrogen,” Journal of Medicinal Chemistry, vol. 43, no. 25, pp. 4768–4780, 2000.
[23]
B. R. Neustadt, J. Hao, N. Lindo et al., “Potent, selective, and orally active adenosine receptor antagonists: arylpiperazine derivatives of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines,” Bioorganic and Medicinal Chemistry Letters, vol. 17, no. 5, pp. 1376–1380, 2007.
[24]
P. G. Baraldi, B. Cacciari, R. Romagnoli, et al., “Pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine derivatives as adenosine receptor ligands: a starting point for searching adenosine receptor antagonists,” Drug Development Research, vol. 53, no. 2-3, pp. 225–235, 2001.
[25]
G. Pastorin, T. Da Ros, G. Spalluto et al., “Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine derivatives as adenosine receptor antagonists. Influence of the N5 substituent on the affinity at the human A3 and adenosine receptor subtypes: a molecular modeling investigation,” Journal of Medicinal Chemistry, vol. 46, no. 20, pp. 4287–4296, 2003.
[26]
K. Varani, S. Merighi, S. Gessi et al., “[3H]MRE 3008F20: a novel antagonist radioligand for the pharmacological and biochemical characterization of human A3 adenosine receptors,” Molecular Pharmacology, vol. 57, no. 5, pp. 968–975, 2000.
[27]
P. G. Baraldi, B. Cacciari, S. Moro et al., “Synthesis, biological activity, and molecular modeling investigation of new pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine derivatives as human A3 adenosine receptor antagonists,” Journal of Medicinal Chemistry, vol. 45, no. 4, pp. 770–780, 2002.
[28]
G. Pastorin, T. Da Ros, C. Bolcato et al., “Synthesis and biological studies of a new series of 5-heteroarylcarbamoylaminopyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidines as human A3 adenosine receptor antagonists. Influence of the heteroaryl substituent on binding affinity and molecular modeling investigations,” Journal of Medicinal Chemistry, vol. 49, no. 5, pp. 1720–1729, 2006.
[29]
S. Moro, P. Braiuca, F. Deflorian et al., “Combined target-based and ligand-based drug design approach as a tool to define a novel 3D-pharmacophore model of human A3 adenosine receptor antagonists: pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine derivatives as a key study,” Journal of Medicinal Chemistry, vol. 48, no. 1, pp. 152–162, 2005.
[30]
A. Maconi, G. Pastorin, T. Da Ros et al., “Synthesis, biological properties, and molecular modeling investigation of the first potent, selective, and water-soluble human A3 adenosine receptor antagonist,” Journal of Medicinal Chemistry, vol. 45, no. 17, pp. 3579–3582, 2002.
[31]
P. G. Baraldi, F. Fruttarolo, M. A. Tabrizi et al., “Design, synthesis, and biological evaluation of C9- and C2-substituted pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines as new and A3 adenosine receptors antagonists,” Journal of Medicinal Chemistry, vol. 46, no. 7, pp. 1229–1241, 2003.
[32]
S. L. Cheong, A. Dolzhenko, S. Kachler et al., “The significance of 2-furyl ring substitution with a 2-(para-substituted) aryl group in a new series of pyrazolo-triazolo-pyrimidines as potent and highly selective hA3 adenosine receptors antagonists: new insights into structure-affinity relationship and receptor-antagonist recognition,” Journal of Medicinal Chemistry, vol. 53, no. 8, pp. 3361–3375, 2010.
[33]
T. Okamura, Y. Kurogi, K. Hashimoto et al., “Structure-activity relationships of adenosine A3 receptor ligands: new potential therapy for the treatment of glaucoma,” Bioorganic and Medicinal Chemistry Letters, vol. 14, no. 14, pp. 3775–3779, 2004.
[34]
V. Colotta, D. Catarzi, F. Varano et al., “1,2,4-triazolo[4,3-a]quinoxalin-1-one: a versatile tool for the synthesis of potent and selective adenosine receptor antagonists,” Journal of Medicinal Chemistry, vol. 43, no. 6, pp. 1158–1164, 2000.
[35]
V. Colotta, D. Catarzi, F. Varano et al., “Synthesis and structure-activity relationships of a new set of 1,2,4-triazolo[4,3-a]quinoxalin-1-one derivatives as adenosine receptor antagonists,” Bioorganic and Medicinal Chemistry, vol. 11, no. 16, pp. 3541–3550, 2003.
[36]
V. Colotta, D. Catarzi, F. Varano et al., “1,2,4-triazolo[4,3-a]quinoxalin-1-one moiety as an attractive scaffold to develop new potent and selective human A3 adenosine receptor antagonists: synthesis, pharmacological, and ligand-receptor modeling studies,” Journal of Medicinal Chemistry, vol. 47, no. 14, pp. 3580–3590, 2004.
[37]
O. Lenzi, V. Colotta, D. Catarzi et al., “4-amido-2-aryl-1,2,4-triazolo[4,3-a]quinoxalin-1-ones as new potent and selective human A3 adenosine receptor antagonists. Synthesis, pharmacological evaluation, and ligand-receptor modeling studies,” Journal of Medicinal Chemistry, vol. 49, no. 13, pp. 3916–3925, 2006.
[38]
V. Colotta, D. Catarzi, F. Varano et al., “Synthesis, ligand-receptor modeling studies and pharmacological evaluation of novel 4-modified-2-aryl-1,2,4-triazolo[4,3-a]quinoxalin-1-one derivatives as potent and selective human A3 adenosine receptor antagonists,” Bioorganic and Medicinal Chemistry, vol. 16, no. 11, pp. 6086–6102, 2008.
[39]
V. Colotta, D. Catarzi, F. Varano et al., “Synthesis and structure-activity relationships of a new set of 2-arylpyrazolo[3,4-c]quinoline derivatives as adenosine receptor antagonists,” Journal of Medicinal Chemistry, vol. 43, no. 16, pp. 3118–3124, 2000.
[40]
V. Colotta, D. Catarzi, F. Varano et al., “New 2-arylpyrazolo[3,4-c]quinoline derivatives as potent and selective human A3 adenosine receptor antagonists. Synthesis, pharmacological evaluation, and ligand-receptor modeling studies,” Journal of Medicinal Chemistry, vol. 50, no. 17, pp. 4061–4074, 2007.
[41]
P. G. Baraldi, M. A. Tabrizi, D. Preti et al., “New 2-arylpyrazolo[4,3-c]quinoline derivatives as potent and selective human A3 adenosine receptor antagonists,” Journal of Medicinal Chemistry, vol. 48, no. 15, pp. 5001–5008, 2005.
[42]
O. Lenzi, V. Colotta, D. Catarzi et al., “2-phenylpyrazolo[4,3-d]pyrimidin-7-one as a new scaffold to obtain potent and selective human a adenosine receptor antagonists: new insights into the receptor-antagonist recognition,” Journal of Medicinal Chemistry, vol. 52, no. 23, pp. 7640–7652, 2009.
[43]
L. P. Davies, S. C. Chow, and J. H. Skerritt, “Pyrazolo[3,4-d]pyrimidines as adenosine antagonists,” Life Sciences, vol. 34, no. 22, pp. 2117–2128, 1984.
[44]
S. A. Poulsen and R. J. Quinn, “Synthesis and structure-activity relationship of pyrazolo[3,4-d]pyrimidines: potent and selective adenosine A1 receptor antagonists,” Journal of Medicinal Chemistry, vol. 39, no. 21, pp. 4156–4161, 1996.
[45]
R. J. Gillespie, I. A. Cliffe, C. E. Dawson et al., “Antagonists of the human adenosine receptor. Part 3: design and synthesis of pyrazolo[3,4-d]pyrimidines, pyrrolo[2,3-d]pyrimidines and 6-arylpurines,” Bioorganic and Medicinal Chemistry Letters, vol. 18, no. 9, pp. 2924–2929, 2008.
[46]
S. Taliani, C. La Motta, L. Mugnaini et al., “Novel N -Substituted pyrazolo[3,4- d]pyrimidine adenosine A receptor antagonists: inhibition of A-Mediated human glioblastoma cell proliferation,” Journal of Medicinal Chemistry, vol. 53, no. 10, pp. 3954–3963, 2010.
[47]
A. Akahane, H. Katayama, T. Mitsunaga et al., “Discovery of FK453, a novel non-xanthine adenosine A1 receptor antagonist,” Bioorganic and Medicinal Chemistry Letters, vol. 6, no. 17, pp. 2059–2062, 1996.
[48]
A. Akahane, H. Katayama, T. Mitsunaga et al., “Discovery of 6-oxo-3 (2-phenylpyrazolo[1,5-a]pyridin-3-yl) 1(6H)-pyridazinebutanoic acid (FK 838): a novel non-xanthine adenosine A1 receptor antagonist with potent diuretic activity,” Journal of Medicinal Chemistry, vol. 42, no. 5, pp. 779–783, 1999.
[49]
S. Kuroda, A. Akahane, H. Itani et al., “Discovery of FR166124, a novel water-soluble pyrazolo[1,5-a]pyridine adenosine A1 receptor antagonist,” Bioorganic and Medicinal Chemistry Letters, vol. 9, no. 14, pp. 1979–1984, 1999.
[50]
B. B. Fredholm, K. Lindstr？m, S. Dionisotti, and E. Ongini, “[3H]SCH 58261, a selective adenosine receptor antagonist, is a useful ligand in autoradiographic studies,” Journal of Neurochemistry, vol. 70, no. 3, pp. 1210–1216, 1998.
[51]
M. El Yacoubi, C. Ledent, M. Parmentier, E. Ongini, J. Costentin, and J. M. Vaugeois, “In vivo labelling of the adenosine receptor in mouse brain using the selective antagonist [3H]SCH 58261,” European Journal of Neuroscience, vol. 14, no. 9, pp. 1567–1570, 2001.
[52]
P. G. Baraldi, B. Cacciari, G. Spalluto et al., “Novel N6-(substituted-phenylcarbamoyl)adenosine- -uronamides as potent agonists for A3 adenosine receptors,” Journal of Medicinal Chemistry, vol. 39, no. 3, pp. 802–806, 1996.
[53]
P. G. Baraldi, B. Cacciari, M. J. P. De Las Infantas et al., “Synthesis and biological activity of a new series of N6-arylcarbamoyl, 2-(Ar)alkynyl-N6-arylcarbamoyl, and N6-carboxamido derivatives of adenosine- -N-ethyluronamide as A1 and A3 adenosine receptor agonists,” Journal of Medicinal Chemistry, vol. 41, no. 17, pp. 3174–3185, 1998.
[54]
S. Gessi, K. Varani, S. Merighi et al., “Pharmacological and biochemical characterization of A3 adenosine receptors in Jurkat T cells,” British Journal of Pharmacology, vol. 134, no. 1, pp. 116–126, 2001.
[55]
S. Gessi, K. Varani, S. Merighi et al., “A3 adenosine receptors in human neutrophils and promyelocytic HL60 cells: a pharmacological and biochemical study,” Molecular Pharmacology, vol. 61, no. 2, pp. 415–424, 2002.
[56]
E. Novellino, E. Abignente, B. Cosimelli et al., “Design, synthesis and biological evaluation of novel N-alkyl- and N-acyl-(7-substituted-2-phenylimidazo[1,2-a][1,3,5]triazin-4-yl)amines (ITAs) as novel A1 adenosine receptor antagonists,” Journal of Medicinal Chemistry, vol. 45, no. 23, pp. 5030–5036, 2002.
