title: 2-Aminopyrimidines as dual adenosine A1/A2A antagonists.
abstract: In this study thirteen 2-aminopyrimidine derivatives were synthesised and screened as potential antagonists of adenosine A1 and A2A receptors in order to further investigate the structure activity relationships of this class of compounds. 4-(5-Methylfuran-2-yl)-6-[3-(piperidine-1-carbonyl)phenyl]pyrimidin-2-amine (8m) was identified as a compound with high affinities for both receptors, with an A2AKi value of 6.34 nM and an A1Ki value of 9.54 nM. The effect of selected compounds on the viability of cultured cells was assessed and preliminary results indicate low cytotoxicity. In vivo efficacy at A2A receptors was illustrated for compounds 8k and 8m since these compounds attenuated haloperidol-induced catalepsy in rats. A molecular docking study revealed that the interactions between the synthesised compounds and the adenosine A2A binding site most likely involve Phe168 and Asn253, interactions which are similar for structurally related adenosine A2A receptor antagonists.
authors.affiliation: 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.
authors.forename: Sarel J
authors.initials: SJ
authors.lastname: Robinson
authors.affiliation: 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.
authors.forename: Jacobus P
authors.initials: JP
authors.lastname: Petzer
authors.affiliation: 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.
authors.forename: Gisella
authors.initials: G
authors.lastname: Terre'Blanche
authors.affiliation: Centre of Excellence for Pharmaceutical Sciences, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
authors.forename: Anél
authors.initials: A
authors.lastname: Petzer
authors.affiliation: Centre of Excellence for Pharmaceutical Sciences, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
authors.forename: Mietha M
authors.initials: MM
authors.lastname: van der Walt
authors.affiliation: 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.
authors.forename: Jacobus J
authors.initials: JJ
authors.lastname: Bergh
authors.affiliation: 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: Arina.Lourens@nwu.ac.za.
authors.forename: Anna C U
authors.initials: AC
authors.lastname: Lourens
mesh_terms: 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; D002375:Catalepsy / Q000139:chemically induced / Q000517:prevention & control; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol; D006367:HeLa Cells; D006801:Humans; D008297:Male; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D011743:Pyrimidines; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; C012180:2-aminopyrimidine; D006220:Haloperidol
keywords: 2-Aminopyrimidine; Adenosine A(1) antagonist; Adenosine A(2A) antagonist; Parkinson's disease