Biological Effects of Morpholin-4-Ium 4 Methoxyphenyl (Morpholino) Phosphinodithioate and Other Phosphorothioate-Based Hydrogen Sulfide Donors.

Significance: Hydrogen sulfide (H ₂ S) is regarded as the third gasotransmitter along with nitric oxide and carbon monoxide. Extensive studies have demonstrated a variety of biological roles for H ₂ S in neurophysiology, cardiovascular disease, endocrine regulation, and other physiological and pathological processes. Recent Advances: Novel H ₂ S donors have proved useful in understanding the biological functions of H ₂ S, with morpholin-4-ium 4 methoxyphenyl (morpholino) phosphinodithioate (GYY4137) being one of the most common pharmacological tools used. One advantage of GYY4137 over sulfide salts is its ability to release H ₂ S in a slow and sustained manner akin to endogenous H ₂ S production, rather than the delivery of H ₂ S as a single concentrated burst. Critical Issues: Here, we summarize recent progress made in the characterization of the biological activities and pharmacological effects of GYY4137 in a range of in vitro and in vivo systems. Recent developments in the structural modification of GYY4137 to generate new compounds and their biological effects are also discussed. Future Directions: Slow-releasing H ₂ S donor, GYY4137, and other phosphorothioate-based H ₂ S donors are potent tools to study the biological functions of H ₂ S. Despite recent progress, more work needs to be performed on these new compounds to unravel the mechanisms behind H ₂ S release and pace of its discharge, as well as to define the effects of by-products of donors after H ₂ S liberation. This will not only lead to better in-depth understanding of the biological effects of H ₂ S but will also shed light on the future development of a new class of therapeutic agents with potential to treat a wide range of human diseases.