ß3-Adrenoceptor-mediated responses in diabetic rat heart.

ß3-adrenoceptors mediate negative inotropic effect in contrast to classical ß1- and ß2-adrenoceptors. Cardiac ß3-adrenoceptors are upregulated in experimental diabetes. Thus, cardiodepressant effect mediated by ß3-adrenoceptors has been proposed to contribute to the impaired cardiac function in this pathology. In our study, we investigated the influence of streptozotocin-diabetes on cardiac contractility to ß3-adrenoceptors stimulation by using Langendorff-perfused rat hearts. BRL 37344, a selective ß3-adrenoceptor agonist, induced dose-dependent decreases in left ventricular developed pressure (LVDP) in hearts from control rats. BRL 37344 also dose-dependently decreased +dP/dt and -dP/dt values. Effects of BRL 37344 were abolished by SR 59230, but not altered by nadolol pre-treatment. On the other hand, these effects of BRL 37344 were all significantly increased in hearts from diabetic rats. We also observed that diabetes significantly increased the mRNA levels encoding cardiac ß3-adrenoceptors. In addition, Giα2 mRNA expressions were found to be increased in the cardiac tissue of diabetic rats as well. The effect of BRL 37344 on cardiac contractility was normalized upon treatment of diabetic rats with insulin. These data demonstrate an increased effect of ß3-adrenoceptor stimulation on hemodynamic function of the heart in accordance with an increased mRNA levels encoding cardiac ß3-adrenoceptors in 8-week diabetic rats.

Thienopyrimidines as ß3-adrenoceptor agonists: hit-to-lead optimization.

Resulting from a vHTS based on a pharmacophore alignment on known ß3-adrenoceptor ligands, an aryloxypropanolamine scaffold comprising a thienopyrimidine moiety was further optimized as a human ß3-AR agonist, yielding a lead compound with an excellent cellular activity of EC(50)=20 pM, selectivity over hß1- and hß2-adrenoceptors and a promising safety profile.