New A(2A) adenosine receptor antagonists in the series of pyrazolo[4,3- e]-1,2,4-triazolo[1,5-c]pyrimidines, bearing oxygenated substituents on the phenylalkyl chains on the 7-position, have been synthesized. The compounds were tested in binding and functional assays to evaluate affinity, potency, and selectivity for rat A(2A) compared to rat A1 and human A3 receptor subtypes. The most interesting compounds (5d,e,h) were tested also in binding to human A1 and A(2A) adenosine receptors. They showed very good affinity (Ki = 0.94 nM for compound 5h) and interesting selectivity with respect to both rA1 and hA3 (compound 5h: rA1/rA(2A) = 787, hA3/rA(2A) > 10 000). These important findings make this new series of compounds the first really selective for A(2A) adenosine receptors. Thermodynamic parameters were evaluated; all the tested compounds displayed an enthalpy-driven binding as expected for antagonists. Moreover, compound 5h showed a negative entropy value. The highly negative enthalpic and entropic contributions could mean that 5h fits very well in the binding site where, probably, an electrostatic interaction is present associated to a scarce solvent reorganization around the receptor binding site. These compounds deserve to be further developed to assess their potential for treatment of neurodegenerative disorders such as Parkinson's disease.

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 A(2A) adenosine receptor antagonists

BARALDI, Pier Giovanni;CACCIARI, Barbara;VARANI, Katia;BOREA, Pier Andrea
1998

Abstract

New A(2A) adenosine receptor antagonists in the series of pyrazolo[4,3- e]-1,2,4-triazolo[1,5-c]pyrimidines, bearing oxygenated substituents on the phenylalkyl chains on the 7-position, have been synthesized. The compounds were tested in binding and functional assays to evaluate affinity, potency, and selectivity for rat A(2A) compared to rat A1 and human A3 receptor subtypes. The most interesting compounds (5d,e,h) were tested also in binding to human A1 and A(2A) adenosine receptors. They showed very good affinity (Ki = 0.94 nM for compound 5h) and interesting selectivity with respect to both rA1 and hA3 (compound 5h: rA1/rA(2A) = 787, hA3/rA(2A) > 10 000). These important findings make this new series of compounds the first really selective for A(2A) adenosine receptors. Thermodynamic parameters were evaluated; all the tested compounds displayed an enthalpy-driven binding as expected for antagonists. Moreover, compound 5h showed a negative entropy value. The highly negative enthalpic and entropic contributions could mean that 5h fits very well in the binding site where, probably, an electrostatic interaction is present associated to a scarce solvent reorganization around the receptor binding site. These compounds deserve to be further developed to assess their potential for treatment of neurodegenerative disorders such as Parkinson's disease.
1998
Baraldi, Pier Giovanni; Cacciari, Barbara; Spalluto, G.; Bergonzoni, M.; Dionisotti, S.; Ongini, E.; Varani, Katia; Borea, Pier Andrea
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/1198441
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