Biased Opioid Ligands

Abstract

Achieving effective pain management is one of the major challenges associated with modern day medicine. Opioids, such as morphine, have been the reference treatment for moderate to severe acute pain not excluding chronic pain modalities. Opioids act through the opioid receptors, the family of G-protein coupled receptors (GPCRs) that mediate pain relief through both the central and peripheral nervous systems. Four types of opioid receptors have been described, including the μ-opioid receptor (MOR), κ-opioid receptor (KOR), δ-opioid receptor (DOR), and the nociceptin opioid peptide receptor (NOP receptor). Despite the proven success of opioids in treating pain, there are still some inherent limitations. All clinically approved MOR analgesics are associated with adverse effects, which include tolerance, dependence, addiction, constipation, and respiratory depression. On the other hand, KOR selective analgesics have found limited clinical utility because they cause sedation, anxiety, dysphoria, and hallucinations. DOR agonists have also been investigated but they have a tendency to cause convulsions. Ligands targeting NOP receptor have been reported in the preclinical literature to be useful as spinal analgesics and as entities against substance abuse disorders while mixed MOR/NOP receptor agonists are useful as analgesics. Ultimately, the goal of opioid-related drug development has always been to design and synthesize derivatives that are equally or more potent than morphine but most importantly are devoid of the dangerous residual side effects and abuse potential. One proposed strategy is to take advantage of biased agonism, in which distinct downstream pathways can be activated by different molecules working through the exact same receptor. It has been proposed that ligands not recruiting β-arrestin 2 or showing a preference for activating a specific G-protein mediated signal transduction pathway will function as safer analgesic across all opioid subtypes. This review will focus on the design and the pharmacological outcomes of biased ligands at the opioid receptors, aiming at achieving functional selectivity.

Keywords: G-protein bias; analgesia; arrestin recruitment; mitragynine; opioid receptors; respiration.

Figure 1

Functional selectivity correlation of opioid agonists. Ligands not recruiting β-arrestin 2 at all opioid subtypes are proposed to dissociate subtype selective adverse effects from its pain-relieving properties. In the case of the μ-opioid receptor (MOR), biased ligands will have less tolerance. For KOR, ligands should have less sedation and anhedonia. Biased DOR agonists should separate convulsions from analgesia while role of biased NOP receptor ligands is less well characterized, although it is possible that memory impairment, sedation, and hypothermia may be dissociated.

Figure 2

Structures of MOR biased ligands reported having different levels of β-arrestin 2 recruitment.

Figure 3

Structures of KOR biased ligands reported having different levels of β-arrestin 2 recruitment.

Figure 4

Structures of DOR biased ligands reported having different levels of β-arrestin 2 recruitment.

Figure 5

Structures of NOP receptor biased ligands reported having different levels of β-arrestin 2 recruitment.