Discovery of 1,3-diethyl-7-methyl-8-(phenoxymethyl)-xanthine derivatives as novel adenosine A1and A2Areceptor antagonists.
Based on a previous report that a series of 8-(phenoxymethyl)-xanthines may be promising leads for the design of A1adenosine receptor antagonists, selected novel and known 1,3-diethyl-7-methyl-8-(phenoxymethyl)-xanthine and 1,3,7-trimethyl-8-(phenoxymethyl)-xanthine analogs were synthesized and evaluated for their A1and A2Aadenosine receptor affinity. Generally, the study compounds exhibited affinity for both the A1and A2Aadenosine receptors. Replacement of the 1,3-dimethyl-substition with a 1,3-diethyl-substition pattern increased A1and A2Abinding affinity. Overall it was found that para-substitution on the phenoxymethyl side-chain of the 1,3-diethyl-xanthines decreased A1affinity except for the 4-Br analog (4f) exhibiting the best A1affinity in the submicromolar range. On the other hand A2Aaffinity for the 1,3-diethyl-xanthines were increased with para-substitution and the 4-OCH3(4b) analog showed the best A2Aaffinity with a Kivalue of 237nM. The 1,3-diethyl-substituted analogs (4a, and 4f) behaved as A1adenosine receptor antagonists in GTP shift assays performed with rat whole brain membranes expressing A1adenosine receptors. This study concludes that para-substituted 1,3-diethyl-7-methyl-8-(phenoxymethyl)-xanthine analogs represent novel A1and A2Aadenosine receptor antagonists that are appropriate for the design of therapies for neurodegenerative disorders such as Parkinson's and Alzheimer's disease.
Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
Rozanne
R
Harmse
Centre of Excellence for Pharmaceutical Sciences, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
Mietha M
MM
van der Walt
Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa; Centre of Excellence for Pharmaceutical Sciences, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
Jacobus P
JP
Petzer
Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa; Centre of Excellence for Pharmaceutical Sciences, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa. Electronic address: Gisella.Terreblanche@nwu.ac.za.
Gisella
G
Terre'Blanche
D058916:Adenosine A1 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D058917:Adenosine A2 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D015394:Molecular Structure; D051381:Rats; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D013329:Structure-Activity Relationship; D019820:Xanthine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D019820:Xanthine
1,3,7-Trimethyl-8-(phenoxymethyl)-xanthines; 1,3-Diethyl-7-methyl-8-(phenoxymethyl)-xanthines; Adenosine A(1) and A(2A) receptor antagonists; Caffeine