Structure-Activity Relationships of Highly Potent and Selective A_2B Adenosine Receptor Agonists

A series comprised of N⁶-substituted adenosines designed from the A_2B adenosine agonist 4 were synthesized and their A_2BR potency was assessed in a cAMP accumulation assay using FlpINCHO cells stably expressing the human A_2BR. This study identified 12 novel A_2BR agonists which exhibited subnanomolar potency at the A_2BR. The most potent compounds possessed a 5'-N-ethyl carboxamide moiety (7, pEC₅₀ = 10.24) or a slightly shorter N⁶-alkyl linker (8, pEC₅₀ = 10.17) relative to 4. Both compounds were also highly receptor subtype selective versus the A₁R, A_2AR, and A₃R. In terms of cellular activity, both the parent 4 and the 5'-N-ethyl carboxamide 7 ameliorated AngII stimulating effects in both cardiac myocytes and fibroblasts. Furthermore, compounds 4 and 7 attenuated TGFβ-stimulated collagen synthesis in cardiac fibroblasts. These antihypertrophy and antifibrotic effects suggest that selective A_2BR compounds may have therapeutic potential for cardiovascular disease where cardiac remodeling is a major driver.