NPC 205 is a potent and selective adenosine A₁, receptor antagonist: Correlation among receptor binding, biochemical, and physiological assays

The chemical synthesis of 8‐aryl‐1,3‐dialkyl derivatives of xanthine and the ability of these compounds to interact with adenosine A₁ and A₂ receptors in vitro (in receptor binding, biochemical, and physiological assays) are described. NPC 205 (1,3‐dipropyl‐8‐[4‐hydroxy‐ phenyl]xanthine) was the most potent and A₁‐selective antagonist of the series. NPC 205 was twice as potent at PACPX (1,3‐dipropyl‐8‐[2‐amino‐4‐chlorophenyl]xanthine) and at least 20‐fold more potent than 8‐phenyltheophylline to inhibit specific binding of [³H]‐cy‐clohexyladenosine to guinea pig and rat brain membranes. Along with NPC 189 (1,3‐dimethyl‐8‐[4‐hydroxyphenyl]xanthine), NPC 200 (1,3‐dipropyl‐8‐phenylxanthine), and PACPX, NPC 205 also was a more potent antagonist of A₁‐receptor‐mediated inhibition of adenylate cyclase (AC) in rat cortex than A₂ receptor‐coupled stimulation of AC in PC‐12 cell membranes. NPC 205 was, in fact, 30‐fold more potent and fourfold more selective than PACPX for the AC‐coupled A₁ receptor function and exhibited competitive interactions with A₁ receptors. In isolated guinea pig atria, NPC 205, NPC 189, NPC 200, and PACPX all reversed 5′N‐ethyl‐carboxamidoadenosine (NECA)‐induced depression of tension and rate. In the Langendorff isolated perfused guinea pig heart preparation, NPC 205 was more potent than PACPX in reversing NECA‐mediated depression in developed tension and rate (A₁‐mediated) and, unlike PACPX, had no effect on coronary perfusion pressure (A₂‐mediated). Neither NPC 205 or PACPX had significant competitive inhibitory effects on rat heart phosphodiesterase III activity in vitro. Together, the results suggest that NPC 205 is a highly potent, selective, and competitive antagonist of adenosine A₁ receptors and should be useful for examining the physiological significance of A₁ receptors in vitro and in vivo.