C2-substituted quinazolinone derivatives exhibit A and/or A adenosine receptor affinities in the low micromolar range.

Antagonists of the adenosine receptors (A and A subtypes) are widely researched as potential drug candidates for their role in Parkinson's disease-related cognitive deficits (A subtype), motor dysfunction (A subtype) and to exhibit neuroprotective properties (A subtype). Previously the benzo-α-pyrone based derivative, 3-phenyl-1H-2-benzopyran-1-one, was found to display both A and A adenosine receptor affinity in the low micromolar range. Prompted by this, the α-pyrone core was structurally modified to explore related benzoxazinone and quinazolinone homologues previously unknown as adenosine receptor antagonists. Overall, the C2-substituted quinazolinone analogues displayed superior A and A adenosine receptor affinity over their C2-substituted benzoxazinone homologues. The benzoxazinones were devoid of A adenosine receptor binding, with only two compounds displaying A adenosine receptor affinity. In turn, the quinazolinones displayed varying degrees of affinity (low micromolar range) towards the A and A adenosine receptor subtypes. The highest A adenosine receptor affinity and selectivity were favoured by methyl para-substitution of phenyl ring B (AK = 2.50 μM). On the other hand, 3,4-dimethoxy substitution of phenyl ring B afforded the best A adenosine receptor binding (AK = 2.81 μM) among the quinazolinones investigated. In conclusion, the quinazolinones are ideal lead compounds for further structural optimization to gain improved adenosine receptor affinity, which may find therapeutic relevance in Parkinson's disease-associated cognitive deficits and motor dysfunctions as well as exerting neuroprotective properties.