title: Selected C8 two-chain linkers enhance the adenosine A1/A2Areceptor affinity and selectivity of caffeine.
abstract: Recent research exploring C8 substitution on the caffeine core identified 8-(2-phenylethyl)-1,3,7-trimethylxanthine as a non-selective adenosine receptor antagonist. To elaborate further, we included various C8 two-chain-length linkers to enhance adenosine receptor affinity. The results indicated that the unsubstituted benzyloxy linker (1e A1Ki= 1.52 μM) displayed the highest affinity for the A1adenosine receptor and the para-chloro-substituted phenoxymethyl (1d A2AKi= 1.33 μM) linker the best A2Aadenosine receptor affinity. The position of the oxygen revealed that the phenoxymethyl linker favoured A1adenosine receptor selectivity over the benzyloxy linker and, by introducing a para-chloro substituent, A2Aadenosine receptor selectivity was obtained. Selected compounds (1c, 1e) behaved as A1adenosine receptor antagonists in GTP shift assays and therefore represent selective and non-selective A1and A2Aadenosine receptor antagonists that may have potential for treating neurological disorders.
authors.affiliation: Centre of Excellence for Pharmaceutical Sciences, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom, 2520, South Africa. Electronic address: dalenevanderwalt@gmail.com.
authors.forename: M M
authors.initials: MM
authors.lastname: van der Walt
authors.affiliation: Centre of Excellence for Pharmaceutical Sciences, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom, 2520, South Africa; Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom, 2520, South Africa.
authors.forename: G
authors.initials: G
authors.lastname: Terre'Blanche
mesh_terms: D058916:Adenosine A1 Receptor Antagonists / Q000737:chemistry*; D058917:Adenosine A2 Receptor Antagonists / Q000737:chemistry*; D002110:Caffeine / Q000737:chemistry* / Q000378:metabolism; D014970:Xanthines / Q000737:chemistry
chemical_list: D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D014970:Xanthines; D002110:Caffeine
keywords: 1,3,7-trimethylxanthine; Adenosine A(1) receptor antagonist; Adenosine A(2A) receptor antagonist; Caffeine; Parkinson's disease