Comparative molecular field analysis (CoMFA) of a series of selective adenosine receptor A2A antagonists

Selective and potent antagonists for the A2A adenosine receptors have been described recently. The most potent compounds have a triazolo‐pyrimidine structure, whereas 8‐styryl‐xanthines usually possess lower affinity at the A2A receptor. We have examined the quantitative structure activity relationships of 34 triazolo‐pyrimidines using the Comparative Molecular Field Analysis (CoMFA). The model developed accounts in a satisfactory manner for the structure‐activity relationships within this series of A2A receptor antagonists (q2 = 0.840, r2 = 0.970) and, consequently, it can be used as a guide in the design of novel analogs with optimized antagonistic activity. The overall predictivity of this model was tested on the published data of a set of external molecules giving acceptable results. The validity of the CoMFA approach as an effective tool for studying the 3D‐QSAR of series of biologically active compounds is confirmed, even if additional efforts clearly are needed for trying to extend the models to structurally more varied series of derivatives. Drug Dev. Res. 46:126–133, 1999. © 1999 Wiley‐Liss, Inc.

[1]  E. Ongini,et al.  Binding of the radioligand [3H]‐SCH 58261, a new non‐xanthine A2A adenosine receptor antagonist, to rat striatal membranes , 1996, British journal of pharmacology.

[2]  G. Spalluto,et al.  Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine derivatives: potent and selective A(2A) adenosine antagonists. , 1996, Journal of medicinal chemistry.

[3]  R A Pearlstein,et al.  Comparative molecular field analysis of selective A3 adenosine receptor agonists. , 1995, Bioorganic & medicinal chemistry.

[4]  E. Ongini.  SCH 58261: A selective A2A adenosine receptor antagonists , 1997 .

[5]  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 A2A adenosine receptor antagonists. , 1998, Journal of medicinal chemistry.

[6]  Stefano Manfredini,et al.  Synthesis 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 A2a adenosine receptor antagonists. , 1994 .

[7]  H. Kase,et al.  Photoisomerization of a potent and selective adenosine A2 antagonist, (E)-1,3-Dipropyl-8-(3,4-dimethoxystyryl)-7-methylxanthine. , 1993, Journal of medicinal chemistry.

[8]  S. Shiozaki,et al.  KF17837: a novel selective adenosine A2A receptor antagonist with anticataleptic activity. , 1994, European journal of pharmacology.

[9]  G. Ghai,et al.  Structure-activity profile of a series of novel triazoloquinazoline adenosine antagonists. , 1988, Journal of medicinal chemistry.

[10]  F Suzuki,et al.  (E)-1,3-dialkyl-7-methyl-8-(3,4,5-trimethoxystyryl)xanthines: potent and selective adenosine A2 antagonists. , 1992, Journal of medicinal chemistry.

[11]  K. Jacobson,et al.  Adenosine A1 and A2 receptors: Structure–function relationships , 1992, Medicinal research reviews.

[12]  R. Cramer,et al.  Validation of the general purpose tripos 5.2 force field , 1989 .

[13]  E. Ongini,et al.  Effects of the new A2 adenosine receptor antagonist 8FB‐PTP, an 8 substituted pyrazolo‐triazolo‐pyrimidine, on in vitro functional models , 1994, British journal of pharmacology.

[14]  G. Spalluto,et al.  1,2,3-Triazolo[5,4-e]1,2,4-triazolo[1,5-c]pyrimidine derivatives: a new class of A2A adenosine receptor antagonists. , 1996, Farmaco.

[15]  S. Moro,et al.  Flavonoid derivatives as adenosine receptor antagonists: a comparison of the hypothetical receptor binding site based on a comparative molecular field analysis model. , 1998, Journal of medicinal chemistry.

[16]  R. G. Browne,et al.  4-Amino[1,2,4]triazolo[4,3-a]quinoxalines. A novel class of potent adenosine receptor antagonists and potential rapid-onset antidepressants. , 1990, Journal of medicinal chemistry.

[17]  C. Müller,et al.  Adenosine receptors and their modulators. , 1993, Pharmaceutica acta Helvetiae.

[18]  G Burnstock,et al.  Nomenclature and Classification of Purinoceptors* , 2005 .

[19]  G. Spalluto,et al.  Synthesis of the tritium labeled SCH 58261, a new non‐xanthine A2A adenosine receptor antagonist , 1996 .

[20]  Barbara Cacciari,et al.  Current Developments of A2a Adenosine Receptor Antagonists , 1995, Current Medicinal Chemistry.

[21]  W. Herzer,et al.  KF17837 is an A2 adenosine receptor antagonist in vivo. , 1993, The Journal of pharmacology and experimental therapeutics.

[22]  Eamonn F. Healy,et al.  Development and use of quantum mechanical molecular models. 76. AM1: a new general purpose quantum mechanical molecular model , 1985 .

[23]  E. Ongini,et al.  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 , 1993 .

[24]  P. Singh,et al.  The in vitro pharmacology of ZM 241385, a potent, non‐xanthine, A2a selective adenosine receptor antagonist , 1995, British journal of pharmacology.

[25]  E. Ongini,et al.  The non-xanthine heterocyclic compound SCH 58261 is a new potent and selective A2a adenosine receptor antagonist. , 1996, The Journal of pharmacology and experimental therapeutics.

[26]  E. Ongini,et al.  (E)-1-(Heterocyclyl or cyclohexyl)-2-[1,3,7-trisubstituted (xanthin-8-yl)] ethenes as A2a adenosine receptor antagonists , 1996 .

[27]  K. Jacobson,et al.  Structure-activity relationships of 1,3-dialkylxanthine derivatives at rat A3 adenosine receptors. , 1994, Journal of medicinal chemistry.

[28]  K. Jacobson,et al.  8‐(3‐Chlorostyryl)caffeine (CSC) is a selective A2‐adenosine antagonist in vitro and in vivo , 1993, FEBS letters.

[29]  H. Kase,et al.  KF17837 ((E)-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine), a potent and selective adenosine A2 receptor antagonist. , 1994, European journal of pharmacology.

[30]  B. Fredholm,et al.  Pharmacology of adenosine A2A receptors. , 1996, Trends in pharmacological sciences.