Structure-affinity relationships of 5'-aromatic ethers and 5'-aromatic sulfides as partial A1 adenosine agonists, potential supraventricular anti-arrhythmic agents

Abstract Atrial fibrillation (AF) is the most commonly encountered sustained clinical arrhythmia with an estimated 2.3 million cases in the US (2001). A 1 adenosine receptor agonists can slow the electrical impulse propagation through the atrioventricular (AV) node (i.e., negative dromotropic effect) resulting in prolongation of the stimulus-to-His bundle (S-H) interval to potentially reduce ventricular rate. Compounds that are full agonists of the A 1 adenosine receptor can cause high grade AV block. Therefore, it is envisioned that a compound that is a partial agonist of the A 1 adenosine receptor could avoid this deleterious effect. 5 ′ Phenyl sulfides (e.g., 17 , EC 50 =1.26 μM) and phenyl ethers (e.g., 28 , EC 50 =0.2 μM) are partial agonists with respect to their AV nodal effects in guinea pig isolated hearts. Additional affinity, GTPγS binding data suggesting partial activity of the A 1 adenosine receptor, and PK results for 5 ′ modified adenosine derivatives are shown.