Opioids are the mainstay for cancer and non-cancer pain management. However, their use is often associated with multiple adverse effects such as drug dependence, respiratory depression, dizziness, urinary retention, and constipation. Among these, the most common and persistent one is probably opioid-induced constipation (OIC). The prevalence of OIC is very high in various populations investigated. Moreover, unlike other adverse effects of opioids, tolerance development to constipation is minimal, and therefore the problem persists and worsens with dose escalation. Peripherally restricted MOR antagonists may alleviate the symptoms of OIC without compromising the analgesic effects of opioids. However, various adverse effects are associated with existing peripheral opioid antagonists, which hinder their application and justify the search for new chemical entities in this category. We hypothesize that a highly selective MOR antagonist with peripherally selective activity will be a suitable drug candidate for further development as an OIC treatment. Three integrated specific aims will test this central hypothesis: 1) to design and synthesize novel ligands as highl selective peripheral MOR antagonists. 2) to determine binding affinity, efficacy, and basic biopharmaceutical/metabolic properties of the new ligands as peripherally restricted MOR antagonists using in vitro assays in a progressive manner; 3) to examine the in vivo potency, efficacy, and PK/PD profiles of novel leads and compare with known drugs to identify drug candidates for further preclinical and clinical studies for OIC treatment.
Morphine, along with other opioids, has been the mainstay for cancer and non-cancer pain management while their most common and persistent adverse effect is probably constipation. This proposal will focus on the development of peripherally selective mu opioid receptor antagonist as novel treatment for opioid induced constipation by applying multidisciplinary tools, including chemical synthesis, medicinal chemistry, molecular modeling, neuropharmacology, and molecular and cellular biology. These studies will build a solid foundation to develop potential clinical candidates as suitable treatments to this disease.
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