Pyrazolo-triazolo-pyrimidines as adenosine receptor antagonists: Effect of the N-5 bond type on the affinity and selectivity at the four adenosine receptor subtypes

In the last few years, many efforts have been made to search for potent and selective human A3 adenosine antagonists. In particular, one of the most promising human A3 adenosine receptor antagonists is represented by the pyrazolo-triazolo-pyrimidine family. This class of compounds has been strongly investigated from the point of view of structure-activity relationships. In particular, it has been observed that fundamental requisites for having both potency and selectivity at the human A3 adenosine receptors are the presence of a small substituent at the N8 position and an unsubstitued phenyl carbamoyl moiety at the N5 position. In this study, we report the role of the N5-bond type on the affinity and selectivity at the four adenosine receptor subtypes. The observed structure-activity relationships of this class of antagonists are also exhaustively rationalized using the recently published ligand-based homology modeling approach.

[1]  Y. Cheng,et al.  Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. , 1973, Biochemical pharmacology.

[2]  R. Lefkowitz,et al.  Validation and statistical analysis of a computer modeling method for quantitative analysis of radioligand binding data for mixtures of pharmacological receptor subtypes. , 1982, Molecular pharmacology.

[3]  M. Levitt Accurate modeling of protein conformation by automatic segment matching. , 1992, Journal of molecular biology.

[4]  G. Stiles,et al.  The A3 adenosine receptor is the unique adenosine receptor which facilitates release of allergic mediators in mast cells. , 1993, The Journal of biological chemistry.

[5]  J. Linden Cloned adenosine A3 receptors: pharmacological properties, species differences and receptor functions. , 1994, Trends in pharmacological sciences.

[6]  I. Biaggioni,et al.  Adenosine A2b receptors evoke interleukin-8 secretion in human mast cells. An enprofylline-sensitive mechanism with implications for asthma. , 1995, The Journal of clinical investigation.

[7]  G. Stiles,et al.  Adenosine receptors: protein and gene structure. , 1995, Archives internationales de pharmacodynamie et de therapie.

[8]  P. Kollman,et al.  A Second Generation Force Field for the Simulation of Proteins, Nucleic Acids, and Organic Molecules , 1995 .

[9]  Thomas A. Halgren Merck molecular force field. I. Basis, form, scope, parameterization, and performance of MMFF94 , 1996, J. Comput. Chem..

[10]  J. Shryock,et al.  Adenosine and adenosine receptors in the cardiovascular system: biochemistry, physiology, and pharmacology. , 1997, The American journal of cardiology.

[11]  B. Fredholm,et al.  Comparative pharmacology of human adenosine receptor subtypes – characterization of stably transfected receptors in CHO cells , 1997, Naunyn-Schmiedeberg's Archives of Pharmacology.

[12]  K. Jacobson,et al.  Adenosine A3 receptors: novel ligands and paradoxical effects. , 1998, Trends in pharmacological sciences.

[13]  D. E. Clark,et al.  Flexible docking using tabu search and an empirical estimate of binding affinity , 1998, Proteins.

[14]  I. Biaggioni,et al.  Pharmacological characterization of adenosine A2B receptors: studies in human mast cells co-expressing A2A and A2B adenosine receptor subtypes. , 1998, Biochemical pharmacology.

[15]  R. Lin,et al.  Stimulation of Adenosine A3 Receptors in Cerebral Ischemia: Neuronal Death, Recovery, or Both? , 1999, Annals of the New York Academy of Sciences.

[16]  G. Spalluto,et al.  Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine derivatives as highly potent and selective human A(3) adenosine receptor antagonists. , 1999, Journal of medicinal chemistry.

[17]  Helmut L. Haas,et al.  Functions of neuronal adenosine receptors , 2000, Naunyn-Schmiedeberg's Archives of Pharmacology.

[18]  S. Moro,et al.  Pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine derivatives as highly potent and selective human A(3) adenosine receptor antagonists: influence of the chain at the N(8) pyrazole nitrogen. , 2000, Journal of medicinal chemistry.

[19]  G. Spalluto,et al.  A3 Adenosine Receptor Ligands: History and Perspectives , 2000, Medicinal research reviews.

[20]  K. Jacobson,et al.  P1 and P2 Purine and Pyrimidine Receptor Ligands , 2001 .

[21]  B. Fredholm,et al.  International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. , 2001, Pharmacological reviews.

[22]  Michael Williams,et al.  Purinergic and Pyrimidinergic Signalling II , 2001, Handbook of Experimental Pharmacology.

[23]  S. Moro,et al.  Fluorosulfonyl- and bis-(beta-chloroethyl)amino-phenylamino functionalized pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine derivatives: irreversible antagonists at the human A3 adenosine receptor and molecular modeling studies. , 2001, Journal of medicinal chemistry.

[24]  Barbara Cacciari,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 A(3) adenosine receptor antagonists. , 2002, Journal of medicinal chemistry.

[25]  S. Moro,et al.  Synthesis, biological properties, and molecular modeling investigation of the first potent, selective, and water-soluble human A(3) adenosine receptor antagonist. , 2002, Journal of medicinal chemistry.

[26]  K. Palczewski,et al.  Crystal Structure of Rhodopsin: A G‐Protein‐Coupled Receptor , 2002, Chembiochem : a European journal of chemical biology.

[27]  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 A(3) adenosine receptor antagonists. , 2002, Journal of medicinal chemistry.

[28]  S. Moro,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 A 3 and A 2B adenosine receptor subtypes: a molecular modeling investigation. , 2003, Journal of medicinal chemistry.

[29]  K. Varani,et al.  A glance at adenosine receptors: novel target for antitumor therapy. , 2003, Pharmacology and Therapeutics.

[30]  C. Müller Medicinal chemistry of adenosine A3 receptor ligands. , 2003, Current topics in medicinal chemistry.

[31]  Darrell R. Abernethy,et al.  International Union of Pharmacology: Approaches to the Nomenclature of Voltage-Gated Ion Channels , 2003, Pharmacological Reviews.

[32]  Francesca Deflorian,et al.  Demystifying the three dimensional structure of G protein-coupled receptors (GPCRs) with the aid of molecular modeling. , 2003, Chemical communications.

[33]  K. Klotz,et al.  Medicinal chemistry and pharmacology of A2B adenosine receptors. , 2003, Current topics in medicinal chemistry.

[34]  Giampiero Spalluto,et al.  Techniques: Recent developments in computer-aided engineering of GPCR ligands using the human adenosine A3 receptor as an example. , 2005, Trends in pharmacological sciences.

[35]  Francesca 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. , 2005, Journal of medicinal chemistry.

[36]  S. Moro,et al.  Novel strategies for the design of new potent and selective human A3 receptor antagonists: an update. , 2006, Current medicinal chemistry.

[37]  Geoffrey Burnstock,et al.  Purinergic signalling , 2012, Acta physiologica.

[38]  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. , 2006, Journal of medicinal chemistry.

[39]  Giampiero Spalluto,et al.  Progress in the pursuit of therapeutic adenosine receptor antagonists , 2006, Medicinal research reviews.

[40]  S. Moro,et al.  Ligand-based homology modeling as attractive tool to inspect GPCR structural plasticity. , 2006, Current pharmaceutical design.

[41]  S. Moro,et al.  G protein-coupled receptors as challenging druggable targets: insights from in silico studies , 2006 .