Barbiturates Are Selective Antagonists at A1Adenosine Receptors

Abstract

Barbiturates in pharmacologically relevant concentrations inhibit binding of (R)‐N⁶‐phenylisopropyl[³H]adenosine ([³H]PIA) to solubilized A₁ adenosine receptors in a concentration‐dependent, stereospecific, and competitive manner. K_i values are similar to those obtained for membrane‐bound receptors and are 31 μM for (±)‐5‐(1,3‐dimethyl)‐5‐ethylbarbituric acid [(±)‐DMBB] and 89 μM for (±)‐pentobarbital. Kinetic experiments demonstrate that barbiturates compete directly for the binding site of the receptor. The inhibition of rat striatal adenylate cyclase by unlabelled (R)‐N⁶‐phenyl‐isopropyladenosine [(R)‐PIA] is antagonized by barbiturates in the same concentrations that inhibit radioligand binding. The stimulation of adenylate cyclase via A₂ adenosine receptors in membranes from N1E 115 neuroblastoma cells is antagonized only by 10–30 times higher concentrations of barbiturates. It is concluded that barbiturates are selective antagonists at the A₁ receptor subtype. In analogy to the excitatory effects of methylxanthines it is suggested that A₁ adenosine receptor antagonism may convey excitatory properties to barbiturates.