MACROCYCLIC AND STABILIZED DYNORPHIN PEPTIDES AS POTENT ANALGESICS FOR IBD PAIN MANAGEMENT

Abstract Acute and chronic abdominal pain are widespread and debilitating symptoms of inflammatory bowel disease (IBD) that substantially decrease patients’ quality of life. Opioids are powerful drugs yet activation of their traditional target, the μ-opioid receptor (MOR) in the central nervous system, is accompanied by severe adverse effects including dependence, sedation and respiratory depression. In recent years, targeting the κ-opioid receptor (KOR) in the periphery emerged as a promising strategy for the development of safer opioid-based analgesics to treat IBD-related pain. We generated cyclized analogues of dynorphin, the endogenous peptide ligand of KOR, and characterized them in pharmacological assays. Our efforts yielded thioether cyclized dynorphin (TCD) showing binding affinity to the KOR in the nanomolar range, with 16- and 150-fold selectivity over the MOR and δ-opioid receptor (DOR), respectively, as determined in radioligand binding assays. In the [35S]GTPγS binding assay, TCD acted as a partial agonist at the KOR when compared to the KOR agonist U69,593, while in the cAMP accumulation assay the peptide had an efficacy exceeding that of dynorphin A1-13. Importantly, TCD exhibits a strong KOR-mediated antinociceptive effect after subcutaneous administration in mouse models of inflammatory pain (formalin-induced inflammatory pain) and visceral pain (acetic acid-induced abdominal writhing test) with an ED50 of around 1.5 μmol/kg, being equipotent to U50,488. Furthermore, TCD did not produce KOR-mediated liability of motor dysfunction/sedation in the rotarod test when given to mice in a 7-fold higher dose than the antinociceptive doses. To obtain a lead compound suitable for oral application, we investigate to increase the stability of TCDs in gastric and intestinal fluids utilizing a medicinal chemistry strategy. Our research has the potential to improve IBD patient care by providing innovative and safer pain drug candidates.