The adenosine A1 and A2A receptor affinity of a series of 3,4-dihydropyrimidone derivatives

Runako M. Katsidzira, Mietha M. van der Walt, Jacobus J. Bergh, Gisella Terre’Blanche


Parkinson’s disease is a complex neurodegenerative condition with current treatment only focussed on symptomatic therapy that does not slow or stop the progression of the disease. Since the discovery that adenosine
A1 and A2A receptors are potential drug targets for the therapy of Parkinson’s disease, various research groups have attempted to identify adenosine antagonists. So the possibility exists that the
administration of an adenosine A2A receptor antagonist may prevent further neurodegeneration. Furthermore, the antagonism of adenosine A1 receptors has the potential of treating Parkinson’s
disease-associated cognitive deficits. Therefore, dual antagonism of adenosine A1 and A2A receptors would be of great benefit since this would potentially treat both the motor as well as the cognitive
impairment associated with Parkinson’s disease. Based on the observation that a series of 1,4-dihydropyridine derivatives possess adenosine A1 and A2A receptor affinity, the current study investigated
the potential of the structurally related 3,4-dihydropyrimidone analogues as adenosine A1 and A2A receptor antagonists. Overall, the 3,4-dihyropyrimidone analogues were found to possess weak affinity
for the adenosine A2A receptor, but more promising adenosine A1 receptor affinity was found, ranging in the low micromolar range. Among the investigated compounds, the p-bromophenyl
substituted dihydropyrimidone (6b) possesses the best adenosine A1 receptor affinity with a Ki value of 7.39 µM. In conclusion, this 3,4-dihydropyrimidone derivative can be used as
a lead for the design of novel adenosine A1 receptor antagonists, although further structural modifications are required to enhance the adenosine A2A receptor affinity before a clinically viable
candidate will be available as potential treatment of Parkinson’s disease.


Adenosien A1-reseptor; Adenosien A2A-reseptor; 3,4-dihidropirimidoon-analoë; Parkinson se siekte; radioligandbindingstudie. / Parkinson's Disease; Adenosine A1-receptor; Adenosine A2A-receptor; 3,4-dihydropyrimidone-analogs

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