Zaprinast is a cGMP-specific phosphodiesterases (PDEs) inhibitor and the lead compound of sildenafil, a potent and selective Zaprinast PDE5 inhibitor and an active drug in the treatment of erectile dysfunction. PDEs hydrolyze the cyclic phosphate bond in cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), and they act to inactivate the cyclic nucleotide signaling pathway. Among them, PDE4, PDE7, and PDE8 are cAMP-specific enzymes, and PDE5, PDE6, and PDE9 are cGMP-specific enzymes. They differ in their mode of action, intracellular distribution, tissue distribution, and relative activity. Regulation of the activity of PDEs is important for controlling intracellular second messenger levels and physiological responses, and zaprinast has been used as a tool to study PDE5 and PDE6.
In addition, zaprinast has been found to act as an agonist for the G protein-coupled receptor GPR35. GPCRs are a large family of cell surface receptors that are important drug targets. Sequencing of the human genome has led to the discovery of new GPCRs, many of which are orphan receptors whose natural ligands have not been identified.GPR35 is one of these orphan GPCRs. It is homologous to a number of purine receptors, GPR23/P2Y9 (receptor for lysophosphatidic acid) and HM74 (receptor for nicotinic acid). Zaprinast is a synthetic GPR35 ligand that can be used to determine the biological function of GPR35.
Osteoporosis is a significant chronic disease. G protein-coupled receptor 35 (GPR35) expression in bone marrow mesenchymal stem cells (BMSCs) was found to be suppressed in osteoporotic mice and patients with confirmed osteoporosis. The overexpression of GPR35 contributes to the proliferation and osteogenesis of BMSCs. Zaprinast is a synthetic GPR35 agonist, and GPR35 may serve as a new target for the agonist Zaprinast may serve as a new drug for the treatment of osteoporosis. Researchers assessed bone mass qualitatively and quantitatively in mice undergoing bilateral ovariectomy (OVX) with or without knockout of the GPR35 gene in the mice (GPR35-/- or GPR35+/+). MicroCT showed that Zaprinast rescued OVX-induced bone loss in GPR35+/+ mice, and Alizarin red and Calcein staining experiments showed consistent results (Fig. 1). Notably, Zaprinast had no significant benefit on bone loss in GPR35-/- mice, implying that the inhibition of OVX-induced bone loss by Zaprinast may be dependent on GPR35. In conclusion, these results suggest that Zaprinast has the potential to be used for the treatment of osteoporosis.
Parkinson's disease (PD) is a common, chronic and incurable neurological disorder. Studies have shown that zaprinast exerts its beneficial effects in Drosophila and human PD models through disease-modifying mechanisms and could be a potential therapeutic agent for PD. Because human PD-related genes are conserved in Drosophila, the Drosophila has become a valuable tool for studying neurodegenerative diseases. DJ-1 is a gene in which mutations trigger early-onset recessive PD. DJ-1β mutant Drosophila exhibit phenotypes associated with PD, including motor deficits, high oxidative stress (OS) levels and metabolic alterations. The researchers found that Zaprinast showed a remarkable ability to inhibit OS-induced cell death. In addition, mitochondrial dysfunction has been linked to the pathogenesis of PD. Three groups of cells were stained using a specific mitochondrial dye (red): control cells, DJ-1 mutant cells, and zaprinast (ZAP)-pretreated DJ-1 mutant cells, and the mitochondrial activity of the cells was quantified by fluorescence intensity. The results showed that Zaprinast increased mitochondrial viability in DJ-1 mutant cells.
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