Date of Award


Document Type


Degree Name

Doctor of Philosophy (Ph.D.)


Pharmaceutical and Chemical Sciences

First Advisor

Mamoun M. Alhamadsheh

First Committee Member

Roshanak Rahimian

Second Committee Member

Miki S. Park

Third Committee Member

Qinliang Zhao

Fourth Committee Member

Melanie Felmlee


Opioid-induced constipation (OIC) is one of the major adverse effects of opioid analgesics used by millions of patients each year. While progress has been made, there remains a significant unmet medical need in the treatment of OIC. Major gaps remain in our understanding of the role of the gastrointestinal tract and central nervous system (CNS) in precipitating OIC. For the last four decades, numerous investigations to study the sites of action of opioid analgesics have utilized peripherally acting mu-opioid receptor antagonists (PAMORAs), which have been incorrectly believed to have limited penetration across the blood-brain barrier (BBB). Several preclinical and clinical reports indicate that significant amounts of PAMORAs penetrate the BBB quite readily. As a result, the usage of current PAMORAs have resulted in misunderstandings of the role of the CNS and gastrointestinal tract in causing side effects such as opioid-induced constipation (OIC).

We have developed a transthyretin-based novel drug delivery approach for restricting the passage of small molecules across the BBB. Our approach involves endowing the opioid agonist/antagonist with the selective transthyretin ligand, AG10. The newly synthesized naloxone- and oxycodone-based conjugates have demonstrated superior peripheral selectivity, improved pharmacokinetics, and efficacy in rats compared to other clinically used PAMORAs. Here we present chemical synthesis, in vitro binding and stability studies, as well as pharmacokinetic and pharmacodynamic evaluations of the AG10-opioid conjugates in rats. Our AG10-based PAMORA allowed us to obtain new insights into the important role of mu-opioid receptors in the central nervous system (CNS) in causing constipation. Additionally, our results demonstrate for the first time that synergy between mu-opioid receptors in the central nervous system and the gastrointestinal tract is crucial to the understanding of OIC and the development of effective treatment regimens. These findings contradict prior ideas that OIC was caused by a mechanism that involves primarily the gastrointestinal mu-opioid receptors. Moreover, we confirmed our findings by a AG10-oxycodone conjugate, a peripherally restricted opioid agonist. This molecule demonstrated the predominant role of CNS in OIC precipitation.

The newly synthesized AG10-opioid conjugates represent a novel class of pharmacological probes that will aid in our understanding of OIC and other undesirable adverse effects of opioids. In addition, these conjugates have been evaluated for their potential therapeutic value in the preclinical studies. Collectively our approach to limit the BBB penetration of opioids will contribute to develop safer and more effective opioid medications.





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