Development of spin-labeled probes for adenosine receptors.
Functionalized xanthine derivatives bearing a nitroxide moiety at the 3- or 8-position were synthesized as electron paramagnetic resonance (EPR) probes. The 8-cyclopentyl-1-propylxanthine derivative 4, spin-labeled at N3 by substitution with a nitroxide-bearing dihydropyrrole moiety, was a potent and selective A(1) adenosine receptor antagonist (K(i) for A(1) 5.5 nM, 1600-fold selectivity vs A(2A), >200-fold vs A(2B), and 310-fold vs A(3) adenosine receptors). 8-(1-Oxyl-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-3-yl)-1,3-dipropylxanthine 10 (K(i) for A(1) 8.2 nM) was similarly potent and selective, while 8-(1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl)-1,3-dipropylxanthine 11 (K(i) for A(1) 160 nM) exhibited significantly lower affinity for A(1) adenosine receptors. 8-[4-(((1-Oxyl-2,2,6,6-tetramethylpiperidin-4-yl)amino)-2-oxoethoxy)phenyl]-1-propylxanthine14, a 3-unsubstituted xanthine derivative, was found to be a potent A(2B) adenosine receptor antagonist (K(i) for A(2B) 48 nM) but also exhibited high affinity for A(1) receptors (K(i) for A(1) 15.7 nM). An X-ray structure of compound 10 was obtained, confirming the proposed structure. The novel spin-labeled A(1)-selective or A(1)/A(2B)-nonselective adenosine receptor antagonists may become useful probes for biophysicochemical investigations of adenosine receptors in their membrane environment.
Ilas
Janez
J
Pharmaceutical Institute, Pharmaceutical Chemistry Poppelsdorf, University of Bonn, Kreuzbergweg 26, D-53113 Bonn, Germany.
Pecar
Slavko
S
Hockemeyer
Jörg
J
Euler
Harald
H
Kirfel
Armin
A
Müller
Christa E
CE
D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D003497:Cyclic N-Oxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D015394:Molecular Structure; D058915:Purinergic P1 Receptor Antagonists; D011869:Radioligand Assay; D051381:Rats; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D043704:Receptor, Adenosine A2B / Q000378:metabolism; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D013113:Spin Labels / Q000138:chemical synthesis*; D013329:Structure-Activity Relationship; D014970:Xanthines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C500077:8-(1-oxyl-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-3-yl)-1,3-dipropylxanthine; C500078:8-(4-(((1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl)amino)-2-oxoethoxy)phenyl)-1-propylxanthine; C500076:8-cyclopentyl-3-(1-oxyl-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-3-ylmethyl)-1-propylxanthine; D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D003497:Cyclic N-Oxides; D003517:Cyclopentanes; D008024:Ligands; D058915:Purinergic P1 Receptor Antagonists; D043682:Receptor, Adenosine A1; D043704:Receptor, Adenosine A2B; D018047:Receptors, Purinergic P1; D013113:Spin Labels; D014970:Xanthines