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dc.contributor.authorPieterse, Lianie
dc.contributor.authorVan der Walt, Mietha M.
dc.contributor.authorTerre'Blanche, Gisella
dc.identifier.citationPieterse, L. et al. 2020. C2-substituted quinazolinone derivatives exhibit A1 and/or A2A adenosine receptor affinities in the low micromolar range. Bioorganic and medicinal chemistry letters, 30(16) #127274. []en_US
dc.description.abstractAntagonists of the adenosine receptors (A1 and A2A subtypes) are widely researched as potential drug candidates for their role in Parkinson’s disease-related cognitive deficits (A1 subtype), motor dysfunction (A2A subtype) and to exhibit neuroprotective properties (A2A subtype). Previously the benzo-α-pyrone based derivative, 3-phenyl-1H-2-benzopyran-1-one, was found to display both A1 and A2A 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 A1 and A2A adenosine receptor affinity over their C2-substituted benzoxazinone homologues. The benzoxazinones were devoid of A2A adenosine receptor binding, with only two compounds displaying A1 adenosine receptor affinity. In turn, the quinazolinones displayed varying degrees of affinity (low micromolar range) towards the A1 and A2A adenosine receptor subtypes. The highest A1 adenosine receptor affinity and selectivity were favoured by methyl para-substitution of phenyl ring B (A1Ki = 2.50 μM). On the other hand, 3,4-dimethoxy substitution of phenyl ring B afforded the best A2A adenosine receptor binding (A2AKi = 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 propertiesen_US
dc.subjectAdenosine A2A receptoren_US
dc.subjectAdenosine A1 receptoren_US
dc.subjectGTP shiften_US
dc.subjectRadioligand binding assayen_US
dc.subjectParkinson's diseaseen_US
dc.titleC2-substituted quinazolinone derivatives exhibit A1 and/or A2A adenosine receptor affinities in the low micromolar rangeen_US
dc.contributor.researchID23347368 - Pieterse, Lianie
dc.contributor.researchID13035134 - Van der Walt, Mietha Magdalena
dc.contributor.researchID10206280 - Terre'Blanche, Gisella

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