Design and in vivo activity of A 3 adenosine receptor agonist prodrugs
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ORIGINAL ARTICLE
Design and in vivo activity of A3 adenosine receptor agonist prodrugs R. Rama Suresh 1 & Shanu Jain 1 & Zhoumou Chen 2,3 & Dilip K. Tosh 1 & Yanling Ma 4 & Maren C. Podszun 4 & Yaron Rotman 4 & Daniela Salvemini 2,3 & Kenneth A. Jacobson 1 Received: 29 April 2020 / Accepted: 7 July 2020 # This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2020
Abstract Prodrugs (MRS7422, MRS7476) of highly selective A3 adenosine receptor (AR) agonists Cl-IB-MECA and MRS5698, respectively, were synthesized by succinylation of the 2′ and 3′ hydroxyl groups, and the parent, active drug was shown to be readily liberated upon incubation with liver esterases. The prodrug MRS7476 had greatly increased aqueous solubility compared with parent MRS5698 and was fully efficacious and with a longer duration than MRS7422 in reversing mouse neuropathic pain (chronic constriction injury model, 3 μmol/kg, p.o.), a known A3AR effect. MRS7476 (5 mg/kg, p.o., twice daily) was found to protect against non-alcoholic steatohepatitis (NASH) in the STAM mouse model, indicated by the NAFLD activity score. Hepatocyte ballooning, IL-10 production, and liver histology were significantly normalized in the MRS7476-treated mice, but not liver fibrosis (no change in ACTA2 levels) or inflammation. Hepatic expression of ADORA3 in human NAFLD patients was 1.9-fold lower compared to normal controls. Adora3 expression determined by qPCR in primary mouse liver was associated with the stellate cells, and its mouse full body A3AR knockout worsened liver markers of inflammation and steatosis. Thus, we have introduced a reversible prodrug strategy that enables water solubility and in vivo activity of masked A3AR agonists in models of two disease conditions. Keywords Purinergic receptors . Nucleosides . Adenosine receptor . Prodrug . Pain . Steatohepatitis
Abbreviations ACTA2 ALT AR AUC
Smooth muscle α actin Alanine transaminase Adenosine receptor Area under the curve
CCI Cl-IB-MECA GPCR HCC
Chronic constriction injury 2-Chloro-N6-(3-iodobenzyl)-adenosine-5′-Nmethyluronamide G protein-coupled receptor Hepatocellular carcinoma
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11302-020-09715-0) contains supplementary material, which is available to authorized users. * Kenneth A. Jacobson [email protected]
Yaron Rotman [email protected]
R. Rama Suresh [email protected] Shanu Jain [email protected]
Daniela Salvemini [email protected] 1
Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bldg. 8A, Rm. B1A-19, 9000 Rockville Pike, Bethesda, MD 20892-0810, USA
Dilip K. Tosh [email protected]
2
Department of Pharmacology and Physiology, Saint Louis University, St. Louis, MO, USA
Yanling Ma [email protected]
3
Henry and Amelia Nasrallah Center for Neuroscience, Saint Louis University, St. Louis, MO, USA
Maren C. Podszun maren.podszu
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