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Review
. 2017 Mar 29;90(1):97-110.
eCollection 2017 Mar.

Novel Molecular Strategies and Targets for Opioid Drug Discovery for the Treatment of Chronic Pain

Keith M Olson  1 , Wei Lei  2 , Attila Keresztes  2 , Justin LaVigne  2 , John M Streicher  2
Affiliations
Review

Novel Molecular Strategies and Targets for Opioid Drug Discovery for the Treatment of Chronic Pain

Keith M Olson et al. Yale J Biol Med. .

Abstract

Opioid drugs like morphine and fentanyl are the gold standard for treating moderate to severe acute and chronic pain. However, opioid drug use can be limited by serious side effects, including constipation, tolerance, respiratory suppression, and addiction. For more than 100 years, we have tried to develop opioids that decrease or eliminate these liabilities, with little success. Recent advances in understanding opioid receptor signal transduction have suggested new possibilities to activate the opioid receptors to cause analgesia, while reducing or eliminating unwanted side effects. These new approaches include designing functionally selective ligands, which activate desired signaling cascades while avoiding signaling cascades that are thought to provoke side effects. It may also be possible to directly modulate downstream signaling through the use of selective activators and inhibitors. Separate from downstream signal transduction, it has also been found that when the opioid system is stimulated, various negative feedback systems are upregulated to compensate, which can drive side effects. This has led to the development of multi-functional molecules that simultaneously activate the opioid receptor while blocking various negative feedback receptor systems including cholecystokinin and neurokinin-1. Other novel approaches include targeting heterodimers of the opioid and other receptor systems which may drive side effects, and making endogenous opioid peptides druggable, which may also reduce opioid mediated side effects. Taken together, these advances in our molecular understanding provide a path forward to break the barrier in producing an opioid with reduced or eliminated side effects, especially addiction, which may provide relief for millions of patients.

Keywords: Chronic Pain; Drug Discovery; Functional Selectivity; Novel Strategies; Novel Targets; Opioid.

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Figures

Figure 1
Figure 1
Summary of Molecular Strategies for Improved Opioid Drug Discovery. Opioid drugs such as morphine and fentanyl activate the MOR, which in turns activates signal transduction cascades. These cascades include factors such as βarrestin2, and drive both analgesia and side effects. At the same time, MOR activation leads to activation of negative feedback receptor systems including CCK, which in turn drive the induction of opioid side effects. This process can be targeted by 1) biased ligands which activate the MOR while blocking or not activating negative signal transduction factors downstream such as βarrestin2; 2) signaling modulators which directly target intracellular signaling molecules to activate or inhibit and improve the opioid response; 3) multi-functional drugs which simultaneously activate the MOR to drive analgesia while blocking negative feedback receptor systems to reduce side effects; and 4) druggable endogenous opioid peptides which have a better activation profile than small molecule drugs like morphine.
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