Multigram-scale syntheses, stability, and photoreactions of A2A adenosine receptor antagonists with 8-styrylxanthine structure: potential drugs for Parkinson's disease.
The improved multigram-scale syntheses of the important 8-styrylxanthine A(2A) adenosine receptor antagonist MSX-2 (8), its water-soluble prodrug MXS-3 (9), and KW-6002 (16) are described. N-Alkylation reactions at different positions of uracil derivatives were optimized. Two different methods for xanthine formation from 6-amino-5-cinnamoylaminouracil precursors were investigated, (a) the elimination of water by alkaline catalysis and (b) hexamethyldisilazane as a condensing agent; the latter was found to be superior. The photosensitivity of 8-styrylxanthines was studied. The (E)-configurated stryrylxanthine MSX-2 (8) isomerized in diluted solution, and the resulting (Z)-isomer (10a) was isolated and characterized. Furthermore, we describe for the first time that solid 8-styrylxanthines can dimerize upon exposition to daylight or irradiation with UV light. The resulting cyclobutane derivatives with head-to-tail (syn) configuration exhibited a considerably lower A(2A) adenosine receptor affinity than their parent compounds. The dimerization product of MSX-2 was a moderately potent nonselective A(1) and A(2A) antagonist (K(i)(A(1)) = 273 nM, K(i) (A(2A)) = 175 nM) while the dimer of the related compound KW-6002 was inactive at A(1) and only weakly active at A(2A) adenosine receptors (K(i) = 1.57 microM). The light sensitivity of 8-styrylxanthine derivatives, not only in solution, but also in the solid state, has to be considered when using those compounds as pharmacological tools or drugs.
Hockemeyer
Jörg
J
University of Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry Poppelsdorf, Kreuzbergweg 26, D-53115 Bonn, Germany.
Burbiel
Joachim C
JC
Müller
Christa E
CE
D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D000978:Antiparkinson Agents / Q000138:chemical synthesis*; D019281:Dimerization; D015394:Molecular Structure; D010777:Photochemistry; D011687:Purines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013343:Styrenes / Q000737:chemistry; D014970:Xanthines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C113601:3-(3-hydroxypropyl)-8-(3-methoxystyryl)-7-methyl-1-propargylxanthine; D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D000978:Antiparkinson Agents; C113602:MSX 3 compound; D011687:Purines; D013343:Styrenes; D014970:Xanthines; C111599:istradefylline