ABSTRACT
8-(Sulfostyryl)xanthine derivatives were synthesized as water-soluble A2A-selective adenosine receptor (AR) antagonists. meta- and para-sulfostyryl-DMPX (3,7-dimethyl-1-propargylxanthine) derivatives 11a and 11b exhibited high affinity to rat A2A-AR in submicromolar concentrations, and were 20- to 30-fold selective versus rat A1-AR. Styryl-DMPX derivatives were inactive at human A2B- and A3-AR. 1,3-Dipropyl-8-p-sulfostyrylxanthine (13) or only a 7-methyl derivative (14) showed similar (13) or higher (14) A2A affinity than 11a and 11b but showed no (13) or only a low degree (14) of selectivity versus A1-, A2B-, and A3-AR. The A2A-selective sulfostyryl-DMPX derivatives exhibit high water-solubility and may be useful research tools for in vivo studies.
Subject(s)
Arylsulfonic Acids/chemical synthesis , Central Nervous System Stimulants/chemical synthesis , Purinergic P1 Receptor Antagonists , Styrenes/chemical synthesis , Xanthines/chemical synthesis , Animals , Arylsulfonic Acids/chemistry , Arylsulfonic Acids/metabolism , Arylsulfonic Acids/pharmacology , CHO Cells , Central Nervous System Stimulants/chemistry , Central Nervous System Stimulants/metabolism , Central Nervous System Stimulants/pharmacology , Cerebral Cortex/metabolism , Cricetinae , Humans , Hydrogen-Ion Concentration , Magnetic Resonance Spectroscopy , Radioligand Assay , Rats , Receptor, Adenosine A2A , Receptors, Purinergic P1/biosynthesis , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/biosynthesis , Solubility , Structure-Activity Relationship , Styrenes/chemistry , Styrenes/metabolism , Styrenes/pharmacology , Xanthines/chemistry , Xanthines/metabolism , Xanthines/pharmacologyABSTRACT
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.