Structure–Activity Relationships of Highly Potent and Selective A _2B Adenosine Receptor Agonists

A series comprised of <i>N</i>⁶-substituted adenosines designed from the A_2B adenosine agonist <b>4</b> 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'-<i>N</i>-ethyl carboxamide moiety (<b>7</b>, pEC₅₀ = 10.24) or a slightly shorter <i>N</i>⁶-alkyl linker (<b>8</b>, pEC₅₀ = 10.17) relative to <b>4</b>. Both compounds were also highly receptor subtype selective versus the A₁R, A_2AR, and A₃R. In terms of cellular activity, both the parent <b>4</b> and the 5'-<i>N</i>-ethyl carboxamide <b>7</b> ameliorated AngII stimulating effects in both cardiac myocytes and fibroblasts. Furthermore, compounds <b>4</b> and <b>7</b> 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.