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

Abstract

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 A_2A 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 A_2A 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 A_2A 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 A_2A receptor affinity, the current study investigated the potential of the structurally related 3,4-dihydropyrimidone analogues as adenosine A₁ and A_2A receptor antagonists. Overall, the 3,4-dihyropyrimidone analogues were found to possess weak affinity for the adenosine A_2A 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 K_i 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 A_2A receptor affinity before a clinically viable candidate will be available as potential treatment of Parkinson’s disease.