Structure-activity relations for presynaptic inhibition of noradrenergic and cholinergic transmission by adenosine: evidence for action on A1 receptors.

1. This study was designed to determine the structure-activity relations for presynaptic inhibition by adenosine of noradrenergic transmission in rat vas deferens and of cholinergic transmission in guinea-pig ileum. 2. The mid-portion of vasa deferentia and segments of ileum were continuously stimulated at 0.2 Hz and the IC50 values of adenosine analogues for inhibition of the twitch responses determined. 3. In both tissues, loss of the 2' and/or 3' hydroxyl groups resulted in a very marked loss of activity, whereas substitution at the 5' position was compatible with considerable activity. 4. In both tissues, an amino group at C6 on the purine moiety was essential for activity. Halide substitutions at the C2 position and bulky substitutions at the N6 position were compatible with increased activity. 5. The L-diastereomer of N6-phenylisopropyladenosine was approximately 100 times more potent that the D-diastereomer in both tissues. 6. It was concluded that adenosine acts at presynaptic receptors with 'R' site characteristics to inhibit noradrenergic and cholinergic transmission and further that these receptors may belong to the A1 subtype.