DORIDOSINE DERIVATIVES - BINDING AT ADENOSINE RECEPTORS AND IN-VIVO EFFECTS

Doridosine, an adenosine analogue, causes, in vivo, hypotension, reduc tion of heart rates, muscle relaxation and anti-inflammatory effects t hrough adenosine A1 and A2 receptors. A series of doridosine derivativ es was synthesized in a search for compounds with more selective adeno sine A1 receptor activity. These derivatives were characterized for bi nding to the respective adenosine receptors and for their cardiovascul ar effects. We used competition binding studies with highly selective radioligands: [H-3]cyclohexyladenosine for adenosine A1 and [H-3]CGS 2 1680 for adenosine A2 binding assays. The results for eight doridosine derivatives revealed that 1-cyclopropylisoguanosine (BN-063) and 1-al lylisoguanosine (AZ-108-1) were more selective for the adenosine A1 re ceptor. In vivo, both BN-063 and AZ-108-1 caused significant bradycard ia but no obvious effect on blood pressure. The bradycardia was almost completely blocked by 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, a sp ecific adenosine A1 receptor antagonist).