Designing Safer Analgesics via μ-Opioid Receptor Pathways

Chan, H.C.; McCarthy, Dillon R.; Li, Jianing; Palczewski, Krzysztof; Yuan, Shuguang

doi:10.1016/j.tips.2017.08.004

Cited by 62 publications

(48 citation statements)

References 73 publications

(119 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…PZM21 is therefore very similar to the prototypic opioid morphine, although in vivo it is less potent. While the current dogma is that, for μ receptor agonists, respiratory depression results from activation of arrestin signalling (see Chan et al ., ; Madariaga‐Mazón et al, ; Roth et al, ; Smith et al, ), there is evidence that signalling through G i /G o is also involved in mediating this behaviour. μ Receptor coupling through G i /G o proteins results in activation of G protein‐activated inwardly rectifying potassium channels (GIRKs) and inhibition of voltage‐gated calcium channels (North and Williams, ; Seward et al, ), and it has been reported that the respiratory depression induced by either DAMGO, applied locally in the ventrolateral medulla, or fentanyl, administered systemically, is attenuated in GIRK2 subunit knockout mice (Montandon et al, ).…”

Section: Discussionmentioning

confidence: 99%

The novel μ‐opioid receptor agonist PZM21 depresses respiration and induces tolerance to antinociception

Hill

Disney

Conibear

et al. 2018

British J Pharmacology

160

157

View full text Add to dashboard Cite

Background and PurposePZM21 is a novel μ‐opioid receptor ligand that has been reported to induce minimal arrestin recruitment and be devoid of the respiratory depressant effects characteristic of classical μ receptor ligands such as morphine. We have re‐examined the signalling profile of PZM21 and its ability to depress respiration.Experimental ApproachG protein (Gi) activation and arrestin‐3 translocation were measured in vitro, using BRET assays, in HEK 293 cells expressing μ receptors. Respiration (rate and tidal volume) was measured in awake, freely moving mice by whole‐body plethysmography, and antinociception was measured by the hot plate test.Key ResultsPZM21 (10−9 – 3 × 10−5 M) produced concentration‐dependent Gi activation and arrestin‐3 translocation. Comparison with responses evoked by morphine and DAMGO revealed that PZM21 was a low efficacy agonist in both signalling assays. PZM21 (10–80 mg·kg−1) depressed respiration in a dose‐dependent manner. The respiratory depression was due to a decrease in the rate of breathing not a decrease in tidal volume. On repeated daily administration of PZM21 (twice daily doses of 40 mg·kg−1), complete tolerance developed to the antinociceptive effect of PZM21 over 3 days but no tolerance developed to its respiratory depressant effect.Conclusion and ImplicationsThese data demonstrate that PZM21 is a low efficacy μ receptor agonist for both G protein and arrestin signalling. Contrary to a previous report, PZM21 depresses respiration in a manner similar to morphine, the classical opioid receptor agonist.

show abstract

Section: Discussionmentioning

confidence: 99%

The novel μ‐opioid receptor agonist PZM21 depresses respiration and induces tolerance to antinociception

Hill

Disney

Conibear

et al. 2018

British J Pharmacology

160

157

View full text Add to dashboard Cite

show abstract

“…In vitro , POMO is a mixed MOR/DOR full agonist, as well as a potent KOR partial agonist. The design of ligands that can act at multiple opioid receptors has emerged as a promising new approach to analgesic drug development to potentially lower side effects and to increase analgesic efficacy, especially in chronic pain conditions ( Ananthan, 2006 ; Kleczkowska et al, 2013 ; Chan et al, 2017 ; Günther et al, 2017 ). All opioid receptors, MOR, DOR, and KOR, are crucial modulators of both nociception and opioid analgesia ( Pasternak, 2014 ; Stein, 2016 ), and are co-localized in nociceptive sensory neurons ( Erbs et al, 2015 ; Massotte, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

In vitro and in vivo Pharmacological Activities of 14-O-Phenylpropyloxymorphone, a Potent Mixed Mu/Delta/Kappa-Opioid Receptor Agonist With Reduced Constipation in Mice

et al. 2018

View full text Add to dashboard Cite

Pain, particularly chronic pain, is still an unsolved medical condition. Central goals in pain control are to provide analgesia of adequate efficacy and to reduce complications associated with the currently available drugs. Opioids are the mainstay for the treatment of moderate to severe pain. However, opioid pain medications also cause detrimental side effects, thus highlighting the need of innovative and safer analgesics. Opioids mediate their actions via the activation of opioid receptors, with the mu-opioid receptor as the primary target for analgesia, but also for side effects. One long-standing focus of drug discovery is the pursuit for new opioids exhibiting a favorable dissociation between analgesia and adverse effects. In this study, we describe the in vitro and in vivo pharmacological profiles of the 14-O-phenylpropyl substituted analog of the mu-opioid agonist 14-O-methyloxymorphone (14-OMO). The consequence of the substitution of the 14-O-methyl in 14-OMO with a 14-O-phenylpropyl group on in vitro binding and functional activity, and in vivo behavioral properties (nociception and gastrointestinal motility) was investigated. In binding studies, 14-O-phenylpropyloxymorphone (POMO) displayed very high affinity at mu-, delta-, and kappa-opioid receptors (Ki values in nM, mu:delta:kappa = 0.073:0.13:0.30) in rodent brain membranes, with complete loss of mu-receptor selectivity compared to 14-OMO. In guinea-pig ileum and mouse vas deferens bioassays, POMO was a highly efficacious and full agonist, being more potent than 14-OMO. In the [35S]GTPγS binding assays with membranes from CHO cells expressing human opioid receptors, POMO was a potent mu/delta-receptor full agonist and a kappa-receptor partial agonist. In vivo, POMO was highly effective in acute thermal nociception (hot-plate test, AD50 = 0.7 nmol/kg) in mice after subcutaneous administration, with over 70- and 9000-fold increased potency than 14-OMO and morphine, respectively. POMO-induced antinociception is mediated through the activation of the mu-opioid receptor, and it does not involve delta- and kappa-opioid receptors. In the charcoal test, POMO produced fourfold less inhibition of the gastrointestinal transit than 14-OMO and morphine. In summary, POMO emerges as a new potent mixed mu/delta/kappa-opioid receptor agonist with reduced liability to cause constipation at antinociceptive doses.

show abstract

“…It facilitates the mutagenesis work, and simplifies the characterization of ligand-binding sites and structural behavior of GPCRs, considering the residue numbering schemes along transmembrane helix residues. The Ballesteros-Weinstein scheme [2] has been more widely accepted for the class A GPCRs over the Oliveira [3], Baldwin [4,5], or Schwartz [6] schemes. This scheme uses two numbers to characterize the residues in each of the seven TM helices: the first number assigns the particular TM helix and the second one corresponds to the residue position related to the most-conserved residue in the particular TM helix which is designated as number 50.…”

Section: The Generic Residue Numbers Of Gpcrsmentioning

confidence: 99%

New Binding Sites, New Opportunities for GPCR Drug Discovery

Chan

Dahoun

et al. 2019

Trends in Biochemical Sciences

Self Cite

112

View full text Add to dashboard Cite

Many central biological events rely on protein-ligand interactions. The identification and characterization of protein-binding sites for ligands are crucial for the understanding of functions of both endogenous ligands and synthetic drug molecules. G protein-coupled receptors (GPCRs) typically detect extracellular signal molecules on the cell surface and transfer these chemical signals across the membrane, inducing downstream cellular responses via G proteins or b-arrestin. GPCRs mediate many central physiological processes, making them important targets for modern drug discovery. Here, we focus on the most recent breakthroughs in finding new binding sites and binding modes of GPCRs and their potentials for the development of new medicines. The Classical Orthosteric Ligand-Binding Site G protein-coupled receptors (GPCRs; see Glossary) play an essential role in many physiological processes, including vision, olfaction and sense of smell, neuronal signal transmission, cell differentiation, pain, muscle contraction, and hormone secretion, to name a few [1-4]. Thus, GPCRs are among the most important targets for modern medicines (Box 1) [5]. Identifying the ligand-binding sites in target GPCRs is the first important step in a structure-based drug development process [6,7]. Recent progress in illuminating structures of GPCRs show that, besides binding to the traditional orthosteric site, ligands could also bind to remote allosteric sites (Table 1) which provide many new opportunities for drug discovery [7-12]. The traditional orthosteric site (Figure 1A) of GPCRs is close to the extracellular region of receptors, between a highly conserved W 6.48Â48 in transmembrane helix 6 (TM6) and extracellular loop 2 (ECL2). To define the relative position of each amino acid in a TM region, the generic residue numbering methods have been introduced for GPCRs (Box 2) [13]. Most residues (Figure 1B) frequently interacting with orthosteric ligands are in TM3 (positions 3.28

show abstract

Designing Safer Analgesics via μ-Opioid Receptor Pathways

Cited by 62 publications

References 73 publications

The novel μ‐opioid receptor agonist PZM21 depresses respiration and induces tolerance to antinociception

The novel μ‐opioid receptor agonist PZM21 depresses respiration and induces tolerance to antinociception

In vitro and in vivo Pharmacological Activities of 14-O-Phenylpropyloxymorphone, a Potent Mixed Mu/Delta/Kappa-Opioid Receptor Agonist With Reduced Constipation in Mice

New Binding Sites, New Opportunities for GPCR Drug Discovery

Contact Info

Product

Resources

About