Recent Advances in the Realm of Allosteric Modulators for Opioid Receptors for Future Therapeutics

Abstract

Opioids, and more specifically μ-opioid receptor (MOR) agonists such as morphine, have long been clinically used as therapeutics for severe pain states but often come with serious side effects such as addiction and tolerance. Many studies have focused on bringing about analgesia from the MOR with attenuated side effects, but its underlying mechanism is not fully understood. Recently, focus has been geared toward the design and elucidation of the orthosteric site with ligands of various biological profiles and mixed subtype opioid activities and selectivities, but targeting the allosteric site is an area of increasing interest. It has been shown that allosteric modulators play key roles in influencing receptor function such as its tolerance to a ligand and affect downstream pathways. There has been a high variance of chemical structures that provide allosteric modulation at a given receptor, but recent studies and reviews tend to focus on the altered cellular mechanisms instead of providing a more rigorous description of the allosteric ligand's structure–function relationship. In this review, we aim to explore recent developments in the structural motifs that potentiate orthosteric binding and their influences on cellular pathways in an effort to present novel approaches to opioid therapeutic design.

Advances in Achieving Opioid Analgesia Without Side Effects

“…For example, it is anticipated that positive allosteric modulators will enhance the activity of endogenous opioid peptides, maintain their temporal and spatial action, and potentially limit the off-target adverse effects. Although several such compounds have been characterized in vitro , their utility in vivo is yet to be determined ( Remesic et al, 2017 ).…”

Insights From Molecular Dynamics Simulations of a Number of G-Protein Coupled Receptor Targets for the Treatment of Pain and Opioid Use Disorders

“…Allosteric modulators of opioid receptors (Remesic et al, 2017) constitute another priority area of research with expected higher probability of success in the development of medications in response to the opioid crisis (Rasmussen et al, 2019). NIDA’s “most wanted” allosteric modulators of opioid receptors include MOP PAMs (Rasmussen et al, 2019).…”

“…One of the reasons why MOP PAMs are of potential interest is that by increasing the potency and/or efficacy of classical opioid drugs, they are expected to produce the same analgesic response achieved by higher doses of opioid drug while simultaneously presenting fewer on-target overdosing risks. Most importantly, these compounds may not be subject to the compensatory mechanisms deriving from chronic MOP activation (e.g., tolerance, dependence, and increased toxicity) because they preserve the temporal and spatial fidelity of signaling in vivo by acting only in the presence of endogenous or other orthosteric ligands (Remesic et al, 2017).…”

Biased versus Partial Agonism in the Search for Safer Opioid Analgesics

“…Different strategies have been developed in the search for safer opioid analgesics, including increasing endogenous opioid signaling with enkephalinase inhibitors [ 3 , 4 ] use of mu opioid receptor positive allosteric modulators [ 5 , 6 ] peripherally restricted opioids [ 7 ] or pH-dependent mu-receptor agonists [ 8 , 9 ] and mixed opioid receptor agonists [ 10 , 11 ]. In addition, mixed agonists for mu and nociceptin/orphanin FQ receptors, showing promising profiles in preclinical studies, have been recently reported in the literature (reviewed in [ 12 ]).…”