Analogues of Adenosine, Theophylline, and Caffeine: Selective Interactions with A₁ and A₂ Adenosine Receptors

Summary

Adenosine modulates a variety of physiological functions through interaction with A₁ and A₂ adenosine receptors, where agonists can mediate inhibition and stimulation, respectively, of adenylate cyclase. Adenosine analogues, in particular the N⁶-substituted compounds, are more potent at A₁ receptors than at A₂ receptors. The subregion of the adenosine receptor that interacts with the N⁶-substituent is different for A₁ and A₂ receptors, particularly with respect to phenyl interactions, bulk tolerance, and stereoselectivity. A series of para-substituted N⁶-phenyladenosines have been synthesized, on the basis of a “functionalized congener” approach in which a chemically reactive group, such as an amine or carboxylic acid, is introduced at the terminus of a chain. From the functionalized congener are synthesized a variety of conjugates, each containing a common pharmacophore. Certain of the adenosine conjugates are highly selective for A₁ receptors. Xanthines are classic antagonists for adenosine receptors, and many of their pharmacological actions may be due to blockade of adenosine receptors. Caffeine and theophylline are virtually nonselective for A₁ and A₂ receptors. Replacement of the methyl groups of theophylline with n-propyl or larger alkyl groups yields xanthines with selectivity for A₁ receptors, particularly when combined with an 8-phenyl moiety. Most 1,3-dialky1-8-phenyl-xanthines are highly water-insoluble, but incorporation of polar aryl substituents, such as parasulfo or para-carboxy, to increase solubility results in a marked reduction in potency and selectivity. A new series of more hydrophilic 1,3-dipropy1-8-phenylxanthines has been synthesized using the functionalized congener approach. Certain conjugates of 8-[4-(carboxymethyloxy)phenyl]-1,3-dipropylxanthine display A₁ selectivity in biochemical and cardiovascular models and in radioactive form provide an antagonist ligand for both A₁ and A₂ receptors. Certain analogues of caffeine in which the methyl group at the 1- or 7-position is replaced with a propargyl or propyl group display selectivity for A₂ receptors. The profile of a series of adenosine analogues or of xanthine antagonists can be used to define the class of adenosine receptors.