Dolcanatide
Uroguanylin with D-amino acids at both ends, made to survive the gut and reach the colon
Dolcanatide (SP-333) is a 16-amino-acid copy of uroguanylin, a gut hormone, with D-asparagine at the start and D-leucine at the end so digestive enzymes break it down more slowly. Like the approved drugs linaclotide and plecanatide it switches on guanylate cyclase-C in the gut lining. It eased colitis in mice and gut pain in rats, and reached phase 2 for opioid-induced constipation, but a 2021 human trial found it did not reach the rectum in active form, and no later trial is registered. It is not approved.
Used in human trials: 27 mg, Once daily, Oral (Oral dolcanatide, healthy volunteers: colorectal activity trial) Details ↓
Recommended Dosing
Used in human trials
No manufacturer dose exists for this use: these are amounts given in published trials, not recommendations.
What is it?
The cells lining the intestine carry a receptor called guanylate cyclase-C. Two hormones made in the gut, guanylin and uroguanylin, switch it on; the receptor then makes cyclic GMP, which drives fluid secretion into the gut and helps keep the lining intact. Two drugs that copy this signal are approved for constipation, linaclotide and plecanatide. Dolcanatide, developed under the code SP-333, is uroguanylin's 16-residue sequence with the first and last amino acids swapped for their D (mirror-image) forms, which digestive enzymes handle poorly. The aim was a version that survives long enough to act along the whole small and large intestine rather than only the upper gut.
The animal work supported that aim. In the 2015 colitis study, dolcanatide and plecanatide both raised cyclic GMP in human colon cancer cells, and once-daily oral doses eased colitis in two mouse models about as well as sulfasalazine or 5-aminosalicylic acid. Dolcanatide held up better in simulated gastric and intestinal fluids, so it was the one chosen to develop further. A 2018 rat study found that both drugs kept cell layers from leaking when exposed to bacterial endotoxin, kept tight-junction proteins in place, and reduced the gut's pain response to colon distension in an inflammatory and a stress model. Reviews from 2013 and 2015 described SP-333 as a candidate for ulcerative colitis.
In people, ClinicalTrials.gov lists a completed single-ascending-dose study of SP-333 tablets in 56 healthy adults (NCT01705938) and a completed 292-person phase 2 dose-ranging trial in opioid-induced constipation (NCT01983306, finished April 2015). Neither has posted results, and no paper reporting them was found on PubMed (searched October 29, 2026). The one human result in print comes from a double-blind, placebo-controlled trial aimed at colorectal cancer prevention: healthy volunteers took 27 mg by mouth daily for 7 days, and the drug did not raise cyclic GMP in the lining cells of the lower rectum. The authors concluded that dolcanatide's extra stability was not enough to act across the colorectum, and that a drug for colorectal cancer prevention would need a formulation released in the colon itself.
No dolcanatide trial has been registered since that one ended in 2021, and the drug is not approved anywhere. It is not sold as a medicine. Anyone with constipation, including constipation caused by opioids, has approved options that act on the same receptor (linaclotide and plecanatide) or other pathways, with labels and dosing a doctor can follow.
At a Glance
Every value in this table is printed from the Grey Peptides dataset, the same record the compound explorer and comparison tool read, so the three can never disagree.
Mechanism of Action
Dolcanatide copies uroguanylin, one of the gut's own hormones for guanylate cyclase-C, with D-amino acids at both ends to slow its breakdown.
Guanylate cyclase-C activation
Binding the receptor on intestinal lining cells raises cyclic GMP, the signal behind fluid secretion; dolcanatide raised cGMP in T84 colon cells (2015 study).
Barrier and pain signalling
It kept cell layers sealed against endotoxin and reduced the pain response to colon distension in rats (2018 study).
Stability in the gut
The D-amino acids made it more resistant to digestive enzymes than plecanatide (2015 study), but not enough to raise cGMP in the human rectum (2021 trial).
Published Research
These are the studies of dolcanatide read from their PubMed abstracts on October 29, 2026: one trial in people, two in rodents and two reviews. The reviews' titles name only the drug class, so they are carded because their abstracts name SP-333 as one of the agents discussed.
27 mg daily did not reach the rectum in active form
In a double-blind, placebo-controlled phase 1 trial, healthy volunteers took 27 mg of oral dolcanatide daily for 7 days. Cyclic GMP in epithelial cells of the distal rectum did not rise, so the drug did not activate its receptor there; the authors judged it unsuitable as given for colorectal cancer prevention.
Colitis in mice
Dolcanatide and plecanatide raised cGMP in T84 cells. Once-daily oral doses of 0.05 to 0.5 mg/kg reduced colitis severity and disease activity in DSS- and TNBS-induced mouse colitis about as well as sulfasalazine or 5-ASA. Dolcanatide resisted simulated gastric and intestinal fluids better and was chosen for further study.
Gut barrier and visceral pain in rats
In cell layers, dolcanatide prevented the leak and the displacement of occludin and ZO-1 caused by bacterial lipopolysaccharide. Given by mouth to rats, it reduced abdominal contractions in response to colon distension after TNBS inflammation and in a restraint-stress model, without changing colon wall elasticity.
Review: guanylyl cyclase C agonists in gut disorders
A review of drugs acting on guanylyl cyclase C in functional gut disorders and inflammatory bowel disease described SP-333 as a promising candidate for ulcerative colitis, alongside plecanatide for constipation.
Review: guanylyl cyclase C agonists for ulcerative colitis
A review of the pharmacology of guanylyl cyclase C agonists for ulcerative colitis named SP-333 among the synthetic agonists, with linaclotide and plecanatide, and set out the case that the receptor supports the colon's mucosal barrier.
Dosing Data
Dolcanatide has no approved label. The row below is the amount given in its one published human trial; the earlier phase 1 and phase 2 sponsor trials have published no amounts or results.
Educational information, not medical advice. Each dose above is tagged with its source: an approved label, a published human study, animal data, or amounts reported by users. None is a recommendation for you. An unapproved compound has no established safe or effective human dose, and products sold for “research use only” are not made or tested for people. Talk to a doctor before acting on anything on this site, including before you start, stop or change any medicine or dose. Full medical disclaimer.
Side Effects & Contraindications
Reported Side Effects
The abstracts read report no side-effect data for dolcanatide in people.
Contraindications & Cautions
No approved label exists, so there are no official contraindications.
Legal Status
Dolcanatide is not approved in any jurisdiction checked.
Frequently Asked Questions
?What is dolcanatide?
An oral copy of the gut hormone uroguanylin with mirror-image amino acids at both ends, made to resist digestion. It activates guanylate cyclase-C, the receptor that linaclotide and plecanatide also target.
?Did it work in people?
The only published human result is negative: 27 mg a day for a week did not activate the receptor in the lining of the lower rectum. Its phase 2 constipation trial finished in 2015 but no results have been posted or published.
?How is it different from plecanatide?
Both are uroguanylin analogues. Plecanatide is approved for constipation; dolcanatide carries D-amino acids for extra stability and was aimed further down the gut, at colitis and the colon.
?Is dolcanatide approved or available?
No. It was never approved, it is not sold as a medicine, and no trial has been registered since 2021.
References
- [other] PubChem CID 91826710, Dolcanatide: formula C65H104N18O26S4, molecular weight 1681.9. Read October 28, 2026. https://pubchem.ncbi.nlm.nih.gov/compound/91826710
- [clinical-trial] Weinberg DS, et al. "Phase I double-blind, placebo-controlled trial of dolcanatide (SP-333) 27 mg to explore colorectal bioactivity in healthy volunteers." Cancer Biol Ther, 2021;22(10-12):544-553. PMID: 34632925.
- [pubmed] Shailubhai K, et al. "Plecanatide and dolcanatide, novel guanylate cyclase-C agonists, ameliorate gastrointestinal inflammation in experimental models of murine colitis." World J Gastrointest Pharmacol Ther, 2015;6(4):213-22. PMID: 26558155.
- [pubmed] Boulete IM, et al. "Oral treatment with plecanatide or dolcanatide attenuates visceral hypersensitivity via activation of guanylate cyclase-C in rat models." World J Gastroenterol, 2018;24(17):1888-1900. PMID: 29740204.
- [pubmed] Jarmuż A, et al. "Emerging treatments in Neurogastroenterology: Perspectives of guanylyl cyclase C agonists use in functional gastrointestinal disorders and inflammatory bowel diseases." Neurogastroenterol Motil, 2015;27(8):1057-68. PMID: 25930667.
- [pubmed] Pitari GM. "Pharmacology and clinical potential of guanylyl cyclase C agonists in the treatment of ulcerative colitis." Drug Des Devel Ther, 2013;7:351-60. PMID: 23637522.
- [registry] ClinicalTrials.gov API v2, read October 28, 2026: NCT01705938 (phase 1, single ascending dose of SP-333 tablets in healthy adults, completed), NCT03300570 (phase 1, dolcanatide in preventing colorectal cancer in healthy volunteers, completed) and NCT01983306 (phase 2, dose-ranging study of SP-333 in opioid-induced constipation, completed).
Sources & Citations
Studies were read from their PubMed records on October 29, 2026. Regulatory status comes from Drugs@FDA and the EMA medicines list (searched October 28, 2026) and trial listings from ClinicalTrials.gov (read October 29, 2026). Sequence, formula and weight are PubChem's. Grey Peptides sells nothing and links to no vendor.
Medical Disclaimer: This content is for educational and informational purposes only. It is not medical advice, and nothing here is an instruction to obtain or use any compound. Consult a licensed healthcare provider before making health decisions.