title: Partial A(1) adenosine receptor agonists from a molecular perspective and their potential use as chronic ventricular rate control agents during atrial fibrillation (AF).
abstract: This review provides a molecular perspective of partial agonism at the A(1) 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 A(1)-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 A(1)-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 A(1)-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 A(1)-adenosine receptor agonism are still needed.
authors.affiliation: CV Therapeutics, Inc, 3172 Porter Dr, Palo Alto, CA 94304, USA. jeff.zablocki@cvt.com
authors.forename: Jeff A
authors.initials: JA
authors.lastname: Zablocki
authors.forename: Lin
authors.initials: L
authors.lastname: Wu
authors.forename: John
authors.initials: J
authors.lastname: Shryock
authors.forename: Luiz
authors.initials: L
authors.lastname: Belardinelli
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D058907:Adenosine A1 Receptor Agonists; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D019277:Entropy; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008024:Ligands; D011487:Protein Conformation; D043682:Receptor, Adenosine A1 / Q000737:chemistry; D043562:Receptors, G-Protein-Coupled / Q000819:agonists; D013329:Structure-Activity Relationship
chemical_list: D058907:Adenosine A1 Receptor Agonists; D000889:Anti-Arrhythmia Agents; D008024:Ligands; D043682:Receptor, Adenosine A1; D043562:Receptors, G-Protein-Coupled; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C048599:N(6)-cyclopentyladenosine; D000241:Adenosine