No description available.

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.

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.