The hybrid molecule, VCP746, is a potent adenosine A_2B receptor agonist that stimulates anti-fibrotic signalling

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• 作者：Elizabeth A. Vecchio^a ; ¹ ; ^{elizabeth.vecchio@monash.edu" class="auth_mail" title="E-mail the corresponding author} ; Chung Hui Chuo^a ; ¹ ; ^{chung.chuo@monash.edu" class="auth_mail" title="E-mail the corresponding author} ; Jo-Anne Baltos^a ; ^{joanne.baltos@monash.edu" class="auth_mail" title="E-mail the corresponding author} ; Leigh Ford^b ; ^{leigh.ford@monash.edu" class="auth_mail" title="E-mail the corresponding author} ; Peter J. Scammells^b ; ^{peter.scammels@monash.edu" class="auth_mail" title="E-mail the corresponding author} ; Bing H. Wang^c ; ^{bing.wang@monash.edu" class="auth_mail" title="E-mail the corresponding author} ; Arthur Christopoulos^a ; ^{arthur.christopoulos@monash.edu" class="auth_mail" title="E-mail the corresponding author} ; Paul J. White^a ; ^{paul.white@monash.edu" class="auth_mail" title="E-mail the corresponding author} ; Lauren T. May^a ; ^{lauren.may@monash.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：NECA (PubChem CID ; 448222) ; BAY60-6583 (PubChem CID ; 11717831) ; DPCPX (PubChem CID ; 1329) ; [3H]DPCPX (PubChem CID ; 53319341) ; PSB-603 (PubChem CID ; 44185871) ; SLV320 (PubChem CID ; 9953065) ; SCH442416 (PubChem CID ; 10668061) ; Angiotensin II (PubChem CID ; 172198) ; TGF-β1 (PubChem CID ; 56842206)
• 刊名：Biochemical Pharmacology
• 出版年：2016
• 出版时间：1 October 2016
• 年：2016
• 卷：117
• 期：Complete
• 页码：46-56
• 全文大小：1957 K

文摘

We have recently described the rationally-designed adenosine receptor agonist, 4-(5-amino-4-benzoyl-3-(3-(trifluoromethyl)phenyl)thiophen-2-yl)-N-(6-(9-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxylmethyl)tetrahydro-furan-2-yl)-9H-purin-6-ylamino)hexyl)benzamide (VCP746), a hybrid molecule consisting of an adenosine moiety linked to an adenosine A₁ receptor (A₁AR) allosteric modulator moiety. At the A₁AR, 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_2BAR). The binding and function of VCP746 at the A_2BAR 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_2BAR, VCP746 was a high affinity, high potency A_2BAR agonist that stimulated G_s- and G_q-mediated signal transduction, with an apparent lack of system bias relative to prototypical A_2BAR agonists. The distinct agonist profile may result from an atypical binding mode of VCP746 at the A_2BAR, which was consistent with a bivalent mechanism of receptor interaction. In isolated neonatal rat cardiac fibroblasts (NCF), VCP746 stimulated potent inhibition of both TGF-β1- and angiotensin II-mediated collagen synthesis. Similar attenuation of TGF-β1-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_2BAR antagonist. Thus, we believe, VCP746 represents an important tool to further investigate the role of the A_2BAR in cardiac (patho)physiology.