Biased mu-opioid receptor ligands: a promising new generation of pain therapeutics

Siuda, Edward R.; Carr, Richard W.; Rominger, David H.; Violin, Jonathan D.

doi:10.1016/j.coph.2016.11.007

Cited by 120 publications

(98 citation statements)

References 67 publications

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“…The concept that agonists could be designed to preferentially couple to Gα i vs β‐arrestin recruitment, referred to as “biased signaling,” was a driving force behind the development of new opiates such as oliceridine . This idea was bolstered by reports showing that β‐arrestin‐2 knockout mice display increased analgesia, decreased tolerance, and have less respiratory depression after morphine administration .…”

Section: Introductionmentioning

confidence: 99%

Synthesis and pharmacological characterization of ethylenediamine synthetic opioids in human μ‐opiate receptor 1 (OPRM1) expressing cells

Hsu

Mallareddy

Yoshida

et al. 2019

Pharmacology Res & Perspec

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Opioids are powerful analgesics acting via the human μ‐opiate receptor (hMOR). Opioid use is associated with adverse effects such as tolerance, addiction, respiratory depression, and constipation. Two synthetic opioids, AH‐7921 and U‐47700 that were developed in the 1970s but never marketed, have recently appeared on the illegal drug market and in forensic toxicology reports. These agents were initially characterized for their analgesic activity in rodents; however, their pharmacology at hMOR has not been delineated. Thus, we synthesized over 50 chemical analogs based on core AH‐7921 and U‐47700 structures to assess for their ability to couple to Gα i signaling and induce hMOR internalization. For both the AH‐7921 and U‐47700 analogs, the 3,4‐dichlorobenzoyl substituents were the most potent with comparable EC 50 values for inhibition of cAMP accumulation; 26.49 ± 11.2 nmol L −1 and 8.8 ± 4.9 nmol L −1 , respectively. Despite similar potencies for Gα i coupling, these two compounds had strikingly different hMOR internalization efficacies: U‐47700 (10 μmol L −1 ) induced ~25% hMOR internalization similar to DAMGO while AH‐7921 (10 μmol L −1 ) induced ~5% hMOR internalization similar to morphine. In addition, the R , R enantiomer of U‐47700 is significantly more potent than the S , S enantiomer at hMOR. In conclusion, these data suggest that U‐47700 and AH‐7921 analogs have high analgesic potential in humans, but with divergent receptor internalization profiles, suggesting that they may exhibit differences in clinical utility or abuse potential.

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Section: Introductionmentioning

confidence: 99%

Synthesis and pharmacological characterization of ethylenediamine synthetic opioids in human μ‐opiate receptor 1 (OPRM1) expressing cells

Hsu

Mallareddy

Yoshida

et al. 2019

Pharmacology Res & Perspec

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“…Fentanyl is an opioid drug used as an analgesic and anaesthetic. It is used for the treatment of acute and severe chronic pain produced by cancer, injuries or surgery as well as in patients with renal failure due to its primarily hepatic elimination . Fentanyl evokes its sedative effect mainly through activation of μ‐opioid receptors, which are abundant in the central nervous system and the peripheral nervous system.…”

Section: Introductionmentioning

confidence: 99%

Polymorphisms associated with fentanyl pharmacokinetics, pharmacodynamics and adverse effects

Saiz‐Rodríguez

Ochoa

Herrador

et al. 2018

Basic Clin Pharma Tox

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Fentanyl is an agonist of the μ‐opioid receptor commonly used in the treatment of moderate‐severe pain. In order to study whether pharmacogenetics explains some of the variability in the response to fentanyl, several genes related to fentanyl receptors, transporters and metabolic enzymes have been analysed. Thirty‐five healthy volunteers (19 men and 16 women) receiving a single 300 μg oral dose of fentanyl were genotyped for 9 polymorphisms in cytochrome P450 (CYP) enzymes (CYP3A4 and CYP3A5), ATP‐binding cassette subfamily B member 1 (ABCB1), opioid receptor mu 1 (OPRM1), catechol‐O‐methyltransferase (COMT) and adrenoceptor beta 2 (ADRB2) by real‐time PCR. Fentanyl concentrations were measured by ultra‐performance liquid chromatography combined with tandem mass spectrometry (UPLC‐MS/MS). Fentanyl pharmacokinetics is affected by sex. Carriers of the CYP3A4*22 allele, which is known to reduce the mRNA expression, showed higher area under the concentration‐time curve (AUC) and lower clearance (Cl) values. Although this finding might be of importance, its validity needs to be confirmed in other similar settings. Furthermore, carriers of the ABCB1 C1236T T/T genotype presented a lower AUC and higher Cl, as well as lower half‐life (T1/2). As volunteers were blocked with naltrexone, the effect of fentanyl on pharmacodynamics might be biased; however, we could observe that fentanyl had a hypotensive effect. Moreover, ADRB2 C523A A allele carriers showed a tendency towards reducing systolic blood pressure. Likewise, OPRM1 and COMT minor allele variants were risk factors for the development of somnolence. CYP3A5*3, ABCB1 C3435T and ABCB1 G2677T/A were not associated with fentanyl's pharmacokinetics, pharmacodynamics and safety profile.

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“…Analgesia is achieved via a classical G-protein pathway which suppresses neuronal excitability and promotes the hyperpolarization of neurons [6]. An agonist -induced conformational change in the μOR instigates the binding of the G i protein, and results in the dissociation of its α subunit from the β and γ subunit complex [7].…”

Section: Signaling Pathways Of the μOrmentioning

confidence: 99%

“…By contrast, most undesirable opioid-mediated effects are related to the β-arrestin pathway, which regulates the desensitization and internalization of the opioid receptor [6,10]. Of the four arrestin subtypes, arrestin-1 and arrestin-4 are visual arrestins that bind to activated and phosphorylated rhodopsin and cone opsin, and terminate phototransduction [11].…”

Section: Signaling Pathways Of the μOrmentioning

confidence: 99%

Designing Safer Analgesics via μ-Opioid Receptor Pathways

Chan

McCarthy

et al. 2017

Trends in Pharmacological Sciences

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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.

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Biased mu-opioid receptor ligands: a promising new generation of pain therapeutics

Cited by 120 publications

References 67 publications

Synthesis and pharmacological characterization of ethylenediamine synthetic opioids in human μ‐opiate receptor 1 (OPRM1) expressing cells

Synthesis and pharmacological characterization of ethylenediamine synthetic opioids in human μ‐opiate receptor 1 (OPRM1) expressing cells

Polymorphisms associated with fentanyl pharmacokinetics, pharmacodynamics and adverse effects

Designing Safer Analgesics via μ-Opioid Receptor Pathways

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