methylnaltrexone and eluxadoline

Opioids have been used for centuries, mostly as a sedative and to treat pain. Currently, they are used on a global scale for the treatment of acute and chronic pain in diseases as osteoarthritis, fibromyalgia, and low back pain. Binding of opioids on opioid receptors can cause a range of different effects such as changes in stress response, analgesia, motor activity and autonomic functions. This review provide a synthetic summary of the most recent literature on the use of drugs acting on mu-receptors to treat two prevalent functional bowel disorders, presenting with opposite bowel habit. Eluxadoline and naloxegol, methylnaltrexone and naldemedine are recently FDA and/or EMA approved drugs demonstrated to be effective and safe for treatment respectively of irritable bowel syndrome subtype diarrhea and opioid induced constipation.

Topics: Analgesics, Opioid; Animals; Antidiarrheals; Constipation; Defecation; Diarrhea; Gastrointestinal Motility; Gastrointestinal Tract; Humans; Imidazoles; Inflammatory Bowel Diseases; Laxatives; Morphinans; Naltrexone; Narcotic Antagonists; Phenylalanine; Polyethylene Glycols; Quaternary Ammonium Compounds; Receptors, Opioid, mu; Signal Transduction

Two 6β- N-heterocyclic naltrexamine derivatives, NAP and NMP, have been identified as peripherally selective mu opioid receptor (MOR) antagonists. To further enhance the peripheral selectivity of both compounds, the 17-amino group and the nitrogen atom of the pyridine ring in both NAP and NMP were methylated to obtain dMNAP and dMNMP, respectively. Compared with NAP and NMP, the binding affinities of dMNAP and dMNMP shifted to MOR and KOR (kappa opioid receptor) dual selective and they acted as moderate efficacy partial agonists. The results from radioligand binding studies were further confirmed by molecular docking studies. In vivo studies demonstrated that dMNAP and dMNMP did not produce antinociception nor did they antagonize morphine's antinociceptive activity, indicating that these compounds did not act on the central nervous system. Meanwhile, both dMNAP and dMNMP significantly slowed down fecal excretion, which indicated that they were peripherally acting opioid receptor agonists. All together, these results suggested that dMNAP and dMNMP acted as peripheral mu/kappa opioid receptor modulators and may be applicable in the treatment of diarrhea in patients with bowel dysfunction.

Topics: Analgesics, Opioid; Animals; CHO Cells; Constipation; Cricetulus; Diarrhea; Drug Partial Agonism; Gastrointestinal Agents; Gastrointestinal Transit; Imidazoles; Methylation; Mice; Molecular Docking Simulation; Morphine; Naltrexone; Narcotic Antagonists; Nociception; Phenylalanine; Quaternary Ammonium Compounds; Radioligand Assay; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu