Adenosine A1/A2A receptor antagonistic properties of selected 2-substituted benzoxazinone and quinazolinone derivatives

Abstract

The A1 and A2A adenosine receptor antagonists are the subject of extensive research based on their aptitude for ameliorating Parkinson’s disease related cognitive deficits (A1 adenosine receptor subtype) and motor dysfunction (A2A adenosine receptor subtype), while also exhibiting neuroprotective properties (A2A adenosine receptor subtype). A benzo-α-pyrone based derivative, 3-phenyl-1H-2-benzopyran-1-one, was previously reported to display both A1 and A2A adenosine receptor affinity in the low micromolar range, thereby, prompting the current investigation of structurally related benzoxazinone and quinazolinone homologues afforded by structural modifications to the benzo-α-pyrone core. Benzoxazinone and quinazolinone derivatives were hitherto not known to be adenosine receptor antagonists. Although the C2-substituted quinazolinone derivatives displayed varying degrees of affinity (low micromolar range), overall they exhibited superior A1 and A2A adenosine receptor affinity (in the low micromolar range) over their C2-substituted benzoxazinone counterparts. The C2-substituted quinazolinone derivative bearing a methyl para-substitution of the phenyl ring B, was documented with the highest affinity and selectivity toward the A1 adenosine receptor (A1Ki = 2.50 μM). In turn, the 3,4-dimethoxy substitution of the phenyl ring B resulted in the best A2A adenosine receptor binding (A2AKi = 2.81 μM). However, amongst the benzoxazinone derivatives only two compounds possessed A1 adenosine receptor activity and displayed a complete lack of A2A adenosine receptor affinity. Therefore, it may be concluded that the quinazolinones are ideal lead compounds for further structural optimization to gain improved adenosine receptor affinity, which may prove to be of value in Parkinson’s disease with regards to neuroprotection and amelioration of the motor dysfunction and cognitive deficits associated with Parkinson’s disease