Potency of N6 secondary and tertiary alkyladenosine analogues at presynaptic A1 adenosine receptors in guinea-pig ileum.

1. The potencies of a series of N6-substituted secondary and tertiary alkyladenosine analogues as inhibitors of the twitch responses of isolated guinea-pig ileum stimulated at 0.2 Hz have been determined. 2. All the analogues tested were full agonists. 3. Since their inhibitory effects were antagonized by theophylline and they had no significant effect on responses of ileum to carbachol, it was concluded that they acted predominantly by causing presynaptic inhibition of transmitter release. 4. Their structure-activity relationships indicated that the S4 subregion of the adenosine receptor in this tissue is capacious enough to accommodate a methyl group while the nature of the secondary alkyl moiety appears to determine the degree to which the tertiary methyl group reduces activity.