Date of Award
2022
Document Type
Dissertation
Degree Name
Doctor of Philosophy (Ph.D.)
Department
Pharmaceutical and Chemical Sciences
First Advisor
Mamoun M. Alhamadsheh
First Committee Member
Miki S. Park
Second Committee Member
Qinliang Zhao
Third Committee Member
Wade Russu
Fourth Committee Member
Jesika Faridi
Abstract
A serious opioid crisis is affecting public health and economics, eroding people’s quality of life. 80% of patients who receive opioids suffer from adverse effects such as Opioid-induced constipation (OIC). However, there is no efficient medicine for these adverse effects. Notably, mainstream theory supports that analgesia effects are mainly controlled by CNS while OIC is predominately controlled by peripheral. In addition, the sites of action of opioid was based on the assumption that mu-opioid receptor antagonists (PAMORAs), did not cross the blood-brain barrier (BBB). Unfortunately, the BBB crossing of PAMORAs mislead the understanding of the role of the central nervous system (CNS) and gastrointestinal tract playing in the adverse effects such as opioid-induced constipation (OIC). Here, we developed a novel technology platform to prevent drugs from crossing the BBB. By applying this technology, naloxone- and oxycodone conjugates demonstrated superior potency, peripheral selectivity, pharmacokinetics, and effectiveness in rats compared to currently clinically used PAMORAs. By the help of these probes, it is revealed for the first time to that the mu-opioid receptors in the CNS played more important role in OIC than the peripheral receptors, which overturned the old theory. And the new theory points the way to better future PAMORAs drug design.
Pages
117
Recommended Citation
Liang, Dengpan. (2022). PERIPHERALLY RESTRICTED DELIVERY SYSTEM PROVIDES INSIGHTS ON THE ROLE OF CNS IN PRECIPITATING OPIOID-INDUCED CONSTIPATION. University of the Pacific, Dissertation. https://scholarlycommons.pacific.edu/uop_etds/3819
Included in
Chemicals and Drugs Commons, Medicinal and Pharmaceutical Chemistry Commons, Other Public Health Commons
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