This review provides a molecular perspective of partial agonism at the A1 adenosine receptor. The structure-activity relationships (SAR) for affinity and intrinsic efficacy of analogues of the full agonist N6-cyclopentyladenosine (CPA) are emphasized. Both general models of activation of G protein-coupled receptors and specific molecular models of the A1-adenosine receptor are used to interpret the results of efforts to synthesize and assay effects of partial agonists. The SAR of affinity and intrinsic efficacy of the 2 ’ , 3 ’ , and especially the 5 ’ -deoxy derivatives of CPA is presented. From this analysis, the nature of the interactions of specific atoms and substituents of the CPA molecule with the A1-adenosine receptor are deduced and presented pictorially. As an example of the therapeutic potential of partial agonists, the design and testing of analogues of CPA to provide chronic ventricular rate control during atrial fibrillation is described. The challenges associated with designing a partial A1-adenosine receptor agonist for providing chronic ventricular rate control during atrial fibrillation are many. To meet these challenges, further medicinal chemistry efforts in the area of partial A1- adenosine receptor agonism are still needed.
Keywords: adenosine, partial, agonist, adenosine a1 receptor, structure activity relationship
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