Adenosine receptors: development of selective agonists and antagonists

Abstract

Adenosine modulates a variety of physiological functions through interaction with A1 and A2 adenosine receptors, where agonists mediate inhibition and stimulation, respectively, of adenylate cyclase. In the cardiovascular system, A2 receptors mediate vasodilation and reduction in blood pressure, while A1 receptors mediate cardiac depression. The involvement of adenylate cyclase in these responses remains unresolved. Adenosine analogs 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 based on 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 classical antagonists for adenosine receptors for many of their pharmacological actions may be due to blockade of adenosine receptors. Caffeine and theophylline are virtually non-selective for A2 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-dialkyl-8-phenyl xanthines are very insoluble, but incorporation of polar aryl substituents, such as sulfo or carboxy to increase solubility, results in marked reduction in potency and selectivity. A new series of more hydrophilic 1,3-dipropyl-8-phenylxanthines has been synthesized using the "functionalized congener" approach. Certain conjugates of 8-[4-(carboxymethyloxy)phenyl 1]1,3-dipropylxanthine display A1 selectivity in biochemical and cardiovascular models. Certain analogs 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 analogs or of xanthine antagonists can be used to define the nature of adenosine receptors.