Müller C E, Geis U, Hipp J, Schobert U, Frobenius W, Pawłowski M, Suzuki F, Sandoval-Ramírez J
Julius-Maximilians-Universität Würzburg, Institut für Pharmazie und Lebensmittelchemie, Pharmazeutische Chemie, Germany.
J Med Chem. 1997 Dec 19;40(26):4396-405. doi: 10.1021/jm970515+.
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.
合成了一系列3,7-二甲基-1-丙炔基黄嘌呤（DMPX）的8-取代衍生物，并将其作为A2A腺苷受体拮抗剂进行研究。探索了制备DMPX衍生物和类似物的不同合成策略。最近开发的一种从3-丙炔基-5,6-二氨基尿嘧啶开始的合成方法被证明是制备这类黄嘌呤衍生物的首选方法。在高亲和力腺苷受体亚型A1和A2A的放射性配体结合研究中对这些新化合物进行了研究，并与标准A2A腺苷受体拮抗剂进行了比较。详细分析了构效关系。鉴定出8-苯乙烯基取代的DMPX衍生物，它们对A2A腺苷受体表现出高亲和力和选择性，包括8-（间氯苯乙烯基）-DMPX（CS-DMPX，Ki A2A = 13 nM，选择性为100倍）、8-（间溴苯乙烯基）-DMPX（BS-DMPX，Ki A2A = 8 nM，选择性为146倍）和8-（3,4-二甲氧基苯乙烯基）-DMPX（Ki A2A = 15 nM, 选择性为167倍）。就A2A亲和力和/或选择性而言，这些及其他新化合物优于标准A2A腺苷受体拮抗剂KF17837（4）和CSC（5）。
