The hybrid molecule, VCP746, is a potent adenosine A2B receptor agonist that stimulates anti-fibrotic signalling

We have recently described the rationally-designed adenosine receptor agonist, 4-(5-amino-4-benzoy13-(3-(trifluoromethyl)phenyl)thiophen-2-yl)-N-(6-(94(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxylmethyl)t etrahydro-furan-2-yl)-9H-purin-6-ylamino)hexyl)benzamide (VCP746), a hybrid molecule consisting of an adenosine moiety linked to an adenosine A(1) receptor (A(1)AR) allosteric modulator moiety. At the A(1)AR, VCP746 mediated cardioprotection in the absence of haemodynamic side effects such as bradycardia. The current study has now identified VCP746 as an important pharmacological tool for the adenosine A(2B) receptor (A(2B)AR). The binding and function of VCP746 at the A(2B)AR was rigorously characterised in a heterologous expression system, in addition to examination of its anti-fibrotic signalling in cardiac- and renal-derived cells. In FlpInCHO cells stably expressing the human A(2B)AR, VCP746 was a high affinity, high potency A2BAR agonist that stimulated G(s)- and G(q)-mediated signal transduction, with an apparent lack of system bias relative to prototypical A(2B)AR agonists. The distinct agonist profile may result from an atypical binding mode of VCP746 at the A(2B)AR, which was consistent with a bivalent mechanism of receptor interaction. In isolated neonatal rat cardiac fibroblasts (NCF), VCP746 stimulated potent inhibition of both TGF-beta 1- and angiotensin II-mediated collagen synthesis. Similar attenuation of TGF-beta 1-mediated collagen synthesis was observed in renal mesangial cells (RMC). The anti-fibrotic signalling mediated by VCP746 in NCF and RMC was selectively reversed in the presence of an A(2B)AR antagonist. Thus, we believe, VCP746 represents an important tool to further investigate the role of the A(2B)AR in cardiac (patho)physiology. (C) 2016 Elsevier Inc. All rights reserved.