Sulprostone is a Selective EP3 Receptor Agonist

Sulprostone (SHB 286), a potent PGE2 analogue, is one of the first EP3 selective agonists. While the half-life of PGE2 in vivo is extremely short, sulprostone (SHB 286) demonstrates an improved stability profile.

PGE2 is the most widely produced in the human body and animal species. It has diverse biologic activities in cell permeability, inflammation, fever and regulation of gastrointestinal mucosa. PGE2 mediates physiological and pathophysiological processes by binding to four different G-protein-coupled receptors (GPCRs): EP1, EP2, EP3 and EP4. The EP receptor subtypes differ in distribution of expression as well as second messenger signaling cascades.

Here, we will introduce a potent PGE2 analogue.

Sulprostone (SHB 286) is a nonsteroidal abortifacient agent. This compound has the potential for the research of pregnancy termination and hemorrhages during delivery.

Morever, PGE2 when combined with proinflammatory cytokines, specifically up-regulates the surface expression levels of the chemokine receptor CCR7 on DCs, which recognizes lymph node–derived chemokines, such as CCL19 and CCL21, exerting a key role for the chemotaxis of DCs.

Sulprostone (SHB 286) has Ki values of 21 nM and 0.6 nM for EP1 and EP3 in cultured chinese hamster ovary cells.

Sulprostone (SHB 286) does not significantly modify the viability and the purity of Dendritic cells (DCs). This compound reduces the expression of CCR7 and impairs migration of DCs. It also has a T1/2 of 0.451 hours, a CL of 56 mL/min•kg, a Vss of 0.583 L/kg and an AUC of 149 ng•h/mL.

Sulprostone (SHB 286) does not adequately induce DC maturation. Indeed, the presence of sulprostone (SHB 286) in the cytohkine cocktail impairs the upregulation of co-stimulatory molecules and maturation markers. It also leads to a reduction of DC migration. Concomitantly, sulprostone (SHB 286) does not significantly modify the viability and the purity of DCs. However it strongly stimulates adhesion decreasing the cells recovery. In conclusion, in vitro maturation of DCs with sulprostone (SHB 286) compromises the DC quality. Then, it affects their use in the GMP protocol for cancer vaccine preparation.

These properties permit the use of sulprostone clinically for pre-operative cervical dilatation, as well as its investigation as a potential antiulcer agent.

Reference:

1. Narumiya, et al. Physiol Rev. 1999;79(4):1193-1226.

2. Bulgarelli J, et al.  Cytotherapy. 2018;20(6):851-860.

3. Shi Y, et al.  J Chromatogr B Analyt Technol Biomed Life Sci. 2018;1092:51-57.