Guanylate Cyclase-C (GC-C, GUCY2C) is a transmembrane receptor, mainly expressed in the intestinal epithelium. It is also considered a tumor suppressor. Endogenous paracrine hormones uroguanylin and guanylin can activate GC-C receptors. The downstream effector of GC-C, cyclic GMP (cGMP), is pH-dependently produced inside the cell, which modulates key physiological functions. These functions include fluid and electrolyte homeostasis, maintenance of the intestinal barrier, anti-inflammatory activity, and regulation of epithelial regeneration. Besides, GC-C is an essential receptor for heat-stable enterotoxins, which makes it become a target for treating acute secretory diarrhea. Moreover, the functions of GC-C are not only limited to the digestive tract, but also in the kidney, cardiovascular system, and even the central nervous system. Here, we will introduce a GC-C agonist, Dolcanatide.

Dolcanatide is an orally active GC-C agonist, with anti-inflammatory activity.

Dolcanatide is an analog of uroguanylin which is an endogenous ligand of GC-C. It can activate the GUCY2C expressed on the apical surface of the cells, GTP and increase the cGMP production. Then the increased cGMP activates PKG-II and inhibits PDE3, thereby cross-activating PKA. Finally, it regulates the ion channel and the ion concentration.

According to the experiments in vitro, the uroguanylin analog can activate GC-C receptors to stimulate cGMP synthesis in T84 cells. Also, Dolcanatide suppresses lipopolysaccharide-induced paracellular permeability in Caco-2 and T84 cells. Besides, Dolcanatide (p.o., 0.01 and 0.05 mg/kg, single dosage) alleviates trinitro-benzene sulfonic acid (TNBS)-induced rectal allodynia in rats. In addition, this agent alleviates stress-induced colorectal hypersensitivity (CRD) in rats.

In conclusion, Dolcanatide is an orally active GC-C agonist, with intestinal anti-inflammatory activity. It has the potential to research gastrointestinal disorders and colorectal cancer.


[1] Boulete IM, et al. World J Gastroenterol. 2018 May 7;24(17):1888-1900.
[2] Shailubhai K, et al. World J Gastrointest Pharmacol Ther. 2015 Nov 6;6(4):213-22.