Review
Designing Safer Analgesics via μ-Opioid Receptor Pathways

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Trends

Pain is a major clinical and economic problem. Owing to the serious side effects associated with current painkillers, the discovery of less toxic medications is an imperative in both academia and industry.

Owing to recent advances in computational and structural biology, several μOR-mediated painkillers with fewer side effects have been successfully designed.

Pain is both a major clinical and economic problem, affecting more people than diabetes, heart disease, and cancer combined. While a variety of prescribed or over-the-counter (OTC) medications are available for pain management, opioid medications, especially those acting on the μ-opioid receptor (μOR) and related pathways, have proven to be the most effective, despite some serious side effects including respiration depression, pruritus, dependence, and constipation. It is therefore imperative that both academia and industry develop novel μOR analgesics which retain their opioid analgesic properties but with fewer or no adverse effects. In this review we outline recent progress towards the discovery of safer opioid analgesics.

Section snippets

Signaling Pathways of the μOR

The opium poppy was known to possess powerful analgesic (see Glossary) properties even in ancient times [1]. It was not until the 19th century that one of its potent analgesic ingredients, morphine, was successfully isolated (Box 1). However, morphine was also shown to have adverse effects on both the respiratory and gastrointestinal (GI) systems. Addiction and tolerance caused by this substance led to strict government regulations for its production, use, and distribution [2]. Pharmacological

Activation Mechanism of μOR

Both antagonist-bound and agonist-bound μOR crystal structures are now available. In the inactive complex (PDB: 4DKL) [15], an irreversible antagonist, β-funaltrexamine (β-FNA), locates at the orthosteric site of the receptor (Figure 2). In the agonist-bound structure, BU72 binds to μOR in a similar way (PDB: 5C1M) [4]. The amino acid conformations in the ligand-binding regions differ subtly. However, the side chain of a highly conserved residue W2936.48 [16], identified as a switch for forming

PZM21: A G-Protein Biased Agonist

While a G-protein biased agonist is bound to μOR, it can induce G protein-mediated analgesia and alleviate undesirable effects caused by the arrestin pathway [27]. The structure-based drug design strategy of PZM21 revealed new binding modes that are worthy of attention. Despite the comment from Manglik et al. that ‘some of the properties of PZM21 (Box 5) were likely to be fortuitous’ [28], PZM21 with its in vivo activities apparently exemplifies a success in rational drug design.

Starting with

Concluding Remarks

Around the globe, pain remains a clinical and economic problem, such that designing safer analgesics has become a vital challenge to both academia and industry. Recent advances in structural and computational biology have allowed the discovery of potentially safer drug candidates which target μOR signaling pathways by different means. Such strategies include the use of G-protein biased molecules such as PZM21, dual functional modulators such as BU08028, pH-sensitive molecules such as NFEPP, and

Glossary

Agonist
a molecule that binds to a receptor which subsequently produces a biological response.
Analgesics
drugs used clinically for pain control. Depending on their mechanism of action and molecular structure, analgesics can be categorized into different classes. Some prototypical examples are provided here. Paracetamol and its structurally related analogs form a commonly used analgesic class. Non-steroidal anti-inflammatory drugs (NSAIDS) and glucocorticoids inhibit the syntheses of

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    • Probing biased activation of mu-opioid receptor by the biased agonist PZM21 using all atom molecular dynamics simulation

      2021, Life Sciences
      Citation Excerpt :

      In our MD simulations, we clearly observed the increased opening of the intracellular interface, which can potentially facilitate G protein binding. But that doesn't mean that other factors can be ruled out, such as decreased arrestin-binding, which closely connects with efficiency of phosphorylation of C-terminal tail, interaction of arrestin to the phosphorylated C terminus, efficiency of receptor sorting into endosomes, etc. [79–81], even though some of these mechanisms affecting arrestin-binding were not analyzed in our MD simulations due to PZM21 being a G protein agonist. In this paper, owing to time and calculation limitations, we simulated only one unbiased agonist (Morphine) vs. G protein biased agonist (PZM21).

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