title: The hybrid molecule, VCP746, is a potent adenosine A2B receptor agonist that stimulates anti-fibrotic signalling.
abstract: 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 A2B receptor (A2BAR). The binding and function of VCP746 at the A2BAR 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 A2BAR, VCP746 was a high affinity, high potency A2BAR agonist that stimulated Gs- and Gq-mediated signal transduction, with an apparent lack of system bias relative to prototypical A2BAR agonists. The distinct agonist profile may result from an atypical binding mode of VCP746 at the A2BAR, 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 A2BAR antagonist. Thus, we believe, VCP746 represents an important tool to further investigate the role of the A2BAR in cardiac (patho)physiology.
authors: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences & Department of Pharmacology, Monash University, Parkville, VIC 3052, Australia. Electronic address: elizabeth.vecchio@monash.edu.
authors: Elizabeth A
authors: EA
authors: Vecchio
authors: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences & Department of Pharmacology, Monash University, Parkville, VIC 3052, Australia. Electronic address: chung.chuo@monash.edu.
authors: Chung Hui
authors: CH
authors: Chuo
authors: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences & Department of Pharmacology, Monash University, Parkville, VIC 3052, Australia. Electronic address: joanne.baltos@monash.edu.
authors: Jo-Anne
authors: JA
authors: Baltos
authors: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia. Electronic address: leigh.ford@monash.edu.
authors: Leigh
authors: L
authors: Ford
authors: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia. Electronic address: peter.scammels@monash.edu.
authors: Peter J
authors: PJ
authors: Scammells
authors: Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC 3004, Australia. Electronic address: bing.wang@monash.edu.
authors: Bing H
authors: BH
authors: Wang
authors: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences & Department of Pharmacology, Monash University, Parkville, VIC 3052, Australia. Electronic address: arthur.christopoulos@monash.edu.
authors: Arthur
authors: A
authors: Christopoulos
authors: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences & Department of Pharmacology, Monash University, Parkville, VIC 3052, Australia. Electronic address: paul.white@monash.edu.
authors: Paul J
authors: PJ
authors: White
authors: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences & Department of Pharmacology, Monash University, Parkville, VIC 3052, Australia. Electronic address: lauren.may@monash.edu.
authors: Lauren T
authors: LT
authors: May
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D058908:Adenosine A2 Receptor Agonists / Q000378:metabolism / Q000494:pharmacology*; D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D000831:Animals, Newborn; D001667:Binding, Competitive; D016466:CHO Cells; D002460:Cell Line; D002478:Cells, Cultured; D003094:Collagen / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D003412:Cricetulus; D005355:Fibrosis; D006801:Humans; D008024:Ligands; D050527:Mesangial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D032386:Myoblasts, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020011:Protective Agents / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D043704:Receptor, Adenosine A2B / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: D058908:Adenosine A2 Receptor Agonists; D008024:Ligands; D020011:Protective Agents; D043704:Receptor, Adenosine A2B; D011994:Recombinant Proteins; D013876:Thiophenes; C000618341:VCP746; D003094:Collagen; D000241:Adenosine
keywords: Adenosine; Adenosine A(2B) receptor; Angiotensin II (PubChem CID: 172198); BAY60-6583 (PubChem CID: 11717831); Bivalent agonist; Collagen; DPCPX (PubChem CID: 1329); Fibroblasts; NECA (PubChem CID: 448222); PSB-603 (PubChem CID: 44185871); SCH442416 (PubChem CID: 10668061); SLV320 (PubChem CID: 9953065); TGF-β1 (PubChem CID: 56842206); [3H]DPCPX (PubChem CID: 53319341)