Effect of linker length and composition on heterobivalent ligand-mediated receptor cross-talk between the A1 adenosine and β2 adrenergic receptors.

Heterobivalent ligands that possess pharmacophores designed to interact with both the A1 adenosine receptor (A1 AR) and the β2 adrenergic receptor (β2 AR) were prepared. More specifically, these ligands contain an adenosine moiety that is linked via its N(6) -position to the amino group of the saligenin-substituted ethanolamine moiety present in the well-known β2 AR agonist, salbutamol. The affinities of these ligands were determined at both receptors and found to vary with linker length and composition. With all compounds, affinity and functional potencies were found to have selectivity for the A1 AR over the β2 AR. In all cases, cAMP accumulation (a β2 AR-mediated response) was mainly observed when the A1 AR was blocked or its function decreased by pertussis toxin or chronic agonist treatment. This suggests that heterobivalent compounds for receptors that mediate opposite responses might be useful for elucidating the mechanisms of receptor cross-talk and how this interaction, in terms of responsiveness, may change under pathophysiological conditions.