Design and in vivo activity of A 3 adenosine receptor agonist prodrugs

Purinergic signalling

article

R. Rama Suresh¹  Shanu Jain¹  Zhoumou Chen²  Dilip K. Tosh¹  Yanling Ma⁴  Maren C. Podszun⁴  Yaron Rotman⁴  Daniela Salvemini²  Kenneth A. Jacobson¹ 

[1] Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health;Department of Pharmacology and Physiology, Saint Louis University;Henry and Amelia Nasrallah Center for Neuroscience, Saint Louis University;Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases

关键词: Purinergic receptors;    Nucleosides;    Adenosine receptor;    Prodrug;    Pain;    Steatohepatitis;   

DOI  :  10.1007/s11302-020-09715-0

学科分类：分子生物学，细胞生物学和基因

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY