Affinity and intrinsic efficacy (IE) of 5′-carbamoyl adenosine analogues for the A1 adenosine receptor—efforts towards the discovery of a chronic ventricular rate control agent for the treatment of atrial fibrillation (AF)

The SAR for the affinity to the A1 adenosine receptor and relative intrinsic efficacy (IE, [35S]-GTPγS binding) of a series of 5′-carbamate and 5′-thionocarbamate derivatives of tecadenoson is described. Based on this SAR, selected compounds were evaluated in guinea pig isolated hearts to determine whether they were partial or full agonists with respect to their negative dromotropism, an A1 AdoR mediated effect. Progress towards obtaining a partial A1 AdoR agonist to potentially control ventricular rate during atrial fibrillation has been made with the discovery of several potent partial A1 AdoR agonists (compounds 13, 14, and 17).