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 hA(3) adenosine receptors antagonists: new insights into structure-affinity relationship and receptor-antagonist recognition

Siew Lee Cheong; Anna Dolzhenko; Sonja Kachler; Silvia Paoletta; Stephanie Federico; Barbara Cacciari; Anton Dolzhenko; Karl-Norbert Klotz; Stefano Moro; Giampiero Spalluto; Giorgia Pastorin

doi:10.1021/jm100049f

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 hA(3) adenosine receptors antagonists: new insights into structure-affinity relationship and receptor-antagonist recognition

J Med Chem. 2010 Apr 22;53(8):3361-75. doi: 10.1021/jm100049f.

Authors

Siew Lee Cheong¹, Anna Dolzhenko, Sonja Kachler, Silvia Paoletta, Stephanie Federico, Barbara Cacciari, Anton Dolzhenko, Karl-Norbert Klotz, Stefano Moro, Giampiero Spalluto, Giorgia Pastorin

Affiliation

¹ Department of Pharmacy, National University of Singapore, 3 Science Drive 2, Block S15, no. 05-PI-03, Singapore 117543.

PMID: 20307065
DOI: 10.1021/jm100049f

Abstract

Among the heterocyclic structures identified as potent human A(3) (hA(3)) adenosine receptor's antagonists, we have demonstrated that the new pyrazolo-triazolo-pyrimidines, bearing an aryl group in replacement of the C(2)-furyl ring, not only confer a good pharmacological profile (with significantly enhanced selectivity against other adenosine receptor subytpes) but also overcome the metabolic transformation of the furan ring into toxic intermediates. All the synthesized [2-(para-substituted) phenyl]-pyrazolo-triazolo-pyrimidines showed affinity at the hA(3) receptor in the low nanomolar range. The most potent derivative of the series presented better affinity and excellent selectivity (compound 31, K(i) hA(3) = 0.108 nM; hA(1)/hA(3) = 5200; hA(2A)/hA(3) = 7200), in comparison to the C(2)-furyl counterpart. A receptor-driven molecular modeling investigation, based on a recently proposed model of A(3) receptor derived from the crystallographic structure of human A(2A) receptor, has been carried out in order to support the experimental binding data and to justify the enhanced selectivity against the other receptor subtypes.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetamides / chemical synthesis*
Acetamides / chemistry
Acetamides / pharmacology
Adenosine A1 Receptor Antagonists
Adenosine A2 Receptor Antagonists
Adenosine A3 Receptor Antagonists*
Adenylyl Cyclases / metabolism
Animals
CHO Cells
Cricetinae
Cricetulus
Furans / chemical synthesis*
Furans / chemistry
Furans / pharmacology
Heterocyclic Compounds, 3-Ring / chemical synthesis*
Heterocyclic Compounds, 3-Ring / chemistry
Heterocyclic Compounds, 3-Ring / pharmacology
Humans
Models, Molecular
Pyrazoles / chemical synthesis*
Pyrazoles / chemistry
Pyrazoles / pharmacology
Pyrimidines / chemical synthesis*
Pyrimidines / chemistry
Pyrimidines / pharmacology
Radioligand Assay
Structure-Activity Relationship
Triazoles / chemical synthesis*
Triazoles / chemistry
Triazoles / pharmacology

Substances

Acetamides
Adenosine A1 Receptor Antagonists
Adenosine A2 Receptor Antagonists
Adenosine A3 Receptor Antagonists
Furans
Heterocyclic Compounds, 3-Ring
N-(2-(phenyl)-8-methylpyrazolo(4,3-e)(1,2,4)triazolo(1,5-c)pyrimidin-5-yl)phenylacetamide
Pyrazoles
Pyrimidines
Triazoles
Adenylyl Cyclases