title: Synthesis and structure-activity relationships of 3,7-dimethyl-1-propargylxanthine derivatives, A2A-selective adenosine receptor antagonists.
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.
authors.affiliation: Julius-Maximilians-Universität Würzburg, Institut für Pharmazie und Lebensmittelchemie, Pharmazeutische Chemie, Germany. mueller@pharmazie.uni-wuerzburg.de
authors.forename: C E
authors.initials: CE
authors.lastname: Müller
authors.forename: U
authors.initials: U
authors.lastname: Geis
authors.forename: J
authors.initials: J
authors.lastname: Hipp
authors.forename: U
authors.initials: U
authors.lastname: Schobert
authors.forename: W
authors.initials: W
authors.lastname: Frobenius
authors.forename: M
authors.initials: M
authors.lastname: Pawłowski
authors.forename: F
authors.initials: F
authors.lastname: Suzuki
authors.forename: J
authors.initials: J
authors.lastname: Sandoval-Ramírez
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D002110:Caffeine / Q000378:metabolism; D015394:Molecular Structure; D010627:Phenethylamines / Q000378:metabolism; D011485:Protein Binding; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D013329:Structure-Activity Relationship; D013805:Theobromine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D014970:Xanthines / Q000378:metabolism
chemical_list: D010627:Phenethylamines; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1; D014970:Xanthines; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; C081198:KF 17837; C027513:N(6)-cyclohexyladenosine; D002110:Caffeine; C057837:3,7-dimethyl-1-propargylxanthine; D000241:Adenosine; D013805:Theobromine