Oxytocin analogues for the oral treatment of abdominal pain

Abdominal pain presents an onerous day-to-day reality for millions of people affected by chronic gastrointestinal disorders such as irritable bowel syndrome (IBS) and inflammatory bowel diseases (IBD). The oxytocin receptor (OTR) has emerged as a potential novel analgesic drug target as OTR expression is upregulated on colon-innervating nociceptors, which are accessible via luminal delivery in chronic visceral hypersensitivity states. However, the low gastrointestinal stability of the endogenous OTR peptide ligand oxytocin (OT) is a crucial bottleneck for therapeutic development. Here, we report the rational development of the first series of fully gut-stable and potent OT analogues, laying the foundation for a new area of oral and gut-specific peptide therapeutics. Compound optimisation guided by systematic structure-gut-stability-activity relationship analysis yielded highly stable analogues (t1/2 >24 h, compared to t1/2 <10 min of OT in intestinal fluid) equipotent to native OT (~3 nM) and with enhanced selectivity for OTR. Colon-targeted local luminal administration of the lead compound significantly reduced colonic mechanical hypersensitivity in a concentration-dependent manner in an in vivo mouse model of chronic abdominal pain. Moreover, oral administration of the lead compound also significantly reduced colonic mechanical hypersensitivity in this abdominal pain model. The employed strategies and generated compounds could pave the way to a new class of gut-specific oral peptide probes and therapeutics to study and combat chronic gastrointestinal disorders, an area with substantial unmet medical needs.