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dc.contributor.authorVan der Walt, Mietha M.
dc.contributor.authorTerre'Blanche, Gisella
dc.identifier.citationVan der Walt, M.M. & Terre'Blanche, G. 2015. 1,3,7-Triethyl-substituted xanthines-possess nanomolar affinity for the adenosine A1 receptor. Bioorganic & medicinal chemistry, 23(20):6641-6649. []en_US
dc.identifier.issn1464-3391 (Online)
dc.description.abstractAdenosine A1 receptors are attracting great interest as drug targets for their role in cognitive deficits. Antagonism of the adenosine A1 receptor may offer therapeutic benefits in complex neurological diseases, such as Alzheimer’s and Parkinson’s disease. The aim of this study was to discover potential selective adenosine A1 receptor antagonists. Several analogs of 8-(3-phenylpropyl)xanthines (3), 8-(2-phenylethyl)xanthines (4) and 8-(phenoxymethyl)xanthines (5) were synthesized and assessed as antagonists of the adenosine A1 and A2A receptors via radioligand binding assays. The results indicated that the 1,3,7-triethyl-substituted analogs (3d, 4d, and 5d), among each series, displayed the highest affinity for the adenosine A1 receptor with Ki values in the nanomolar range. This ethyl-substitution pattern was previously unknown to enhance adenosine A1 receptor binding affinity. The 1,3,7-triethyl-substituted analogs (3d, 4d, and 5d) behaved as adenosine A1 receptor antagonists in GTP shift assays performed with either rat cortical or whole brain membranes expressing adenosine A1 receptors. Further, in vivo evaluation of 3d showed reversal of adenosine A1 receptor agonist-induced hypolocomotion. In conclusion, the most potent evaluated compound, 8-(3-phenylpropyl)-1,3,7-triethylxanthine (3d), showed both in vitro and in vivo activity, and therefore represent a novel adenosine A1 receptor antagonist that may have potential as a drug candidate for dementia disordersen_US
dc.description.sponsorshipNational Research Foundation (NRF) and Medical Research Council (MRC) of South Africaen_US
dc.subjectAlzheimer’s diseaseen_US
dc.subjectParkinson’s diseaseen_US
dc.subjectGTP shift assayen_US
dc.subjectAdenosine A1 receptorsen_US
dc.title1,3,7-Triethyl-substituted xanthines-possess nanomolar affinity for the adenosine A1 receptoren_US
dc.contributor.researchID13035134 - Van der Walt, Mietha Magdalena
dc.contributor.researchID10206280 - Terre'Blanche, Gisella

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