Design and in vivo activity of A3 adenosine receptor agonist prodrugs

Abstract

Prodrugs (MRS7422, MRS7476) of highly selective A 3 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 A 3 AR 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 A 3 AR 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 A 3 AR agonists in models of two disease conditions. KeywordsPurinergic receptors . Nucleosides . Adenosine receptor . Prodrug . Pain . Steatohepatitis Abbreviations ACTA2 Smooth muscle α actin ALT Alanine transaminase AR Adenosine receptor AUC Area under the curve CCI Chronic constriction injury Cl-IB-MECA 2-Chloro-N 6 -(3-iodobenzyl)-adenosine-5′-Nmethyluronamide GPCR G protein-coupled receptor HCC Hepatocellular carcinoma

Targeting Adenosine Receptors: A Potential Pharmacological Avenue for Acute and Chronic Pain

“…In another model of nerve injury that produces tactile allodynia, the daily administration of IB-MECA averted the appearance of hypersensitivities, the activation of glial cells and the altered transmission of nociceptive stimuli, resulting in an attenuation of neuropathic pain [ 120 ]. In a recent study, MRS7476, a prodrug with increased aqueous solubility compared with parent MRS5698, was found to be efficacious in reversing neuropathic pain induced by CCI [ 121 ].…”

Metabolic roles of G protein‐coupled receptor signaling in obesity and type 2 diabetes

“…Similarly, treatment (p.o.) of STAM mice with MRS7476, another A 3 receptor agonist, protected against NASH development [124]. Further, A 3 receptor null mice maintained on a HFD showed increased gene expression of liver steatosis and inflammation markers, supporting the role of this receptor in the pathophysiology of NAFLD/NASH [124].…”

“…of STAM mice with MRS7476, another A 3 receptor agonist, protected against NASH development [124]. Further, A 3 receptor null mice maintained on a HFD showed increased gene expression of liver steatosis and inflammation markers, supporting the role of this receptor in the pathophysiology of NAFLD/NASH [124]. Currently, a clinical trial is underway to investigate the efficacy of Cl‐IB‐MECA, another A 3 receptor agonist, in the treatment of NASH [125].…”

Purinergic Signaling in Liver Pathophysiology

“…Recent studies have highlighted the importance of the A 3 AR in NAFLD/NASH. A 3 AR expression in livers from NAFLD patients was decreased by 1.9-fold compared to controls, highlighting a plausible role of the receptor in NAFLD pathophysiology ( 69 ). Global deficiency of A 3 AR in mice fed a HFD enhanced expression of genes involved in hepatic inflammation and steatosis ( 69 ) ( Figure 1 ).…”