Trends in Pharmacological Sciences
ReviewDesigning Safer Analgesics via μ-Opioid Receptor Pathways
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
References (79)
Mu opioid receptor: a gateway to drug addiction
Curr. Opin. Neurobiol.
(2004)Structural insights into the dynamic process of beta2-adrenergic receptor signaling
Cell
(2015)Allostatic mechanisms of opioid tolerance beyond desensitization and downregulation
Trends Pharmacol. Sci.
(2016)Structural mimicry in class A G protein-coupled receptor rotamer toggle switches: the importance of the F3.36(201)/W6.48(357) interaction in cannabinoid CB1 receptor activation
J. Biol. Chem.
(2004)Generic GPCR residue numbers – aligning topology maps while minding the gaps
Trends Pharmacol. Sci.
(2015)Orphanin FQ/nociceptin blocks acquisition of morphine place preference
Brain Res.
(1999)The dynamic process of beta2-adrenergic receptor activation
Cell
(2013)The biology of the opioid growth factor receptor (OGFr)
Brain Res. Brain Res. Rev.
(2002)- et al.
Mu opioid receptors in pain management
Acta Anaesthesiol. Taiwan.
(2011) G protein-coupled receptors: dynamic machines for signaling pain and itch
Neuron
(2015)
An overview of the diverse roles of G-protein coupled receptors (GPCRs) in the pathophysiology of various human diseases
Biotechnol. Adv.
Allosteric sodium in class A GPCR signaling
Trends Biochem. Sci.
G protein coupled receptor structure and activation
Biochim. Biophys. Acta
Biased agonism of the mu-opioid receptor by TRV130 increases analgesia and reduces on-target adverse effects versus morphine: a randomized, double-blind, placebo-controlled, crossover study in healthy volunteers
Pain
Acetaminophen from liver to brain: new insights into drug pharmacological action and toxicity
Pharmacol. Res.
Acetaminophen and ondansetron: the central serotonergic connection
J. Clin. Anesth.
Neuropathic pain: principles of diagnosis and treatment
Mayo Clin. Proc.
The neurobiology of opioid dependence: implications for treatment
Sci. Pract. Perspect.
Opioid receptors
Annu. Rev. Med.
Structural insights into mu-opioid receptor activation
Nature
Mu opioids and their receptors: evolution of a concept
Pharmacol. Rev.
Biased mu-opioid receptor ligands: a promising new generation of pain therapeutics
Curr. Opin. Pharmacol.
Crystal structure of the beta2 adrenergic receptor-Gs protein complex
Nature
Biological membranes
Essays Biochem.
Structure-based discovery of opioid analgesics with reduced side effects
Nature
The role of beta-arrestins in the termination and transduction of G-protein-coupled receptor signals
J. Cell Sci.
G-protein-coupled receptor phosphorylation: where, when and by whom
Br. J. Pharmacol.
Structure of active beta-arrestin-1 bound to a G-protein-coupled receptor phosphopeptide
Nature
Crystal structure of the micro-opioid receptor bound to a morphinan antagonist
Nature
Action of molecular switches in GPCRs – theoretical and experimental studies
Curr. Med. Chem.
The molecular mechanism of P2Y1 receptor activation
Angew. Chem. Int. Ed. Engl.
Mechanistic studies on the stereoselectivity of the serotonin 5-HT1A receptor
Angew. Chem. Int. Ed. Engl.
Effect of a toggle switch mutation in TM6 of the human adenosine A(3) receptor on Gi protein-dependent signalling and Gi-independent receptor internalization
Br. J. Pharmacol.
W246 opens a gate for a continuous intrinsic water pathway during activation of the adenosine A receptor
Angew. Chem. Int. Ed. Engl.
Crystal structure of the beta2 adrenergic receptor–Gs protein complex
Nature
Activation and allosteric modulation of a muscarinic acetylcholine receptor
Nature
Observation of ‘ionic lock’ formation in molecular dynamics simulations of wild-type beta 1 and beta 2 adrenergic receptors
Biochemistry
Structure–function of the G protein-coupled receptor superfamily
Annu. Rev. Pharmacol. Toxicol.
G-protein-coupled receptors: sustained signaling via intracellular megaplexes and pathway-specific drugs
Angew. Chem. Int. Ed. Engl.
Cited by (56)
Quantification of observable behaviors following oral administration of oxycodone and nalfurafine in male rhesus monkeys
2023, Drug and Alcohol DependenceBifunctional μ opioid and σ<inf>1</inf> receptor ligands as novel analgesics with reduced side effects
2021, European Journal of Medicinal ChemistryProbing biased activation of mu-opioid receptor by the biased agonist PZM21 using all atom molecular dynamics simulation
2021, Life SciencesCitation 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).