Synthesis and structure-activity relationships of 3,7-dimethyl-1-propargylxanthine derivatives, A2A-selective adenosine receptor antagonists |
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Authors: | CE Müller U Geis J Hipp U Schobert W Frobenius M Paw?owski F Suzuki J Sandoval-Ramírez |
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Affiliation: | Julius-Maximilians-Universit?t Würzburg, Institut für Pharmazie und Lebensmittelchemie, Pharmazeutische Chemie, Germany. mueller@pharmazie.uni-wuerzburg.de |
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Abstract: | A series of 8-substituted derivatives of 3,7-dimethyl-1-propargylxanthine (DMPX) was synthesized and investigated as A2A adenosine receptor antagonists. Different synthetic strategies for the preparation of DMPX derivatives and analogues were explored. A recently developed synthetic procedure starting from 3-propargyl-5,6-diaminouracil proved to be the method of choice for the preparation of this type of xanthine derivatives. The novel compounds were investigated in radioligand binding studies at the high-affinity adenosine receptor subtypes A1 and A2A and compared with standard A2A adenosine receptor antagonists. Structure-activity relationships were analyzed in detail. 8-Styryl-substituted DMPX derivatives were identified that exhibit high affinity and selectivity for A2A adenosine receptors, including 8-(m-chlorostyryl)-DMPX (CS-DMPX, Ki A2A = 13 nM, 100-fold selective), 8-(m-bromostyryl)-DMPX (BS-DMPX, Ki A2A = 8 nM, 146-fold selective), and 8-(3,4-dimethoxystyryl)-DMPX (Ki A2A = 15 nM, 167-fold selective). These and other novel compounds are superior to the standard A2A adenosine receptor antagonists KF17837 (4) and CSC (5) with respect to A2A affinity and/or selectivity. |
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