Article
Biochemistry & Molecular Biology
Diniz M. Sena Jr, Xiaojing Cong, Alejandro Giorgetti
Summary: This study utilized enhanced sampling molecular dynamics simulations to investigate the structural changes of MOR when bound to different ligands, revealing that agonists and antagonists have different effects on the activation state of the receptor. Despite not observing a complete transition to the active state, an important conformational change was observed.
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
(2021)
Article
Pharmacology & Pharmacy
Keith M. Olson, Andrea L. Devereaux, Payal Chatterjee, Savanah L. Saldana-Shumaker, Amanda Shafer, Adam Plotkin, Ram Kandasamy, Alexander D. MacKerell, John R. Traynor, Christopher W. Cunningham
Summary: This study investigates the structure-activity relationships of benzylideneoxymorphone analogs in order to develop analgesics with reduced tolerance and side effects. One compound, nitro-BOM (NBOM), showed high-efficacy antinociception but also exhibited tolerance and toxicity upon repeated administration. Despite these issues, NBOM provides an important tool for understanding MOPr/DOPr pharmacology.
FRONTIERS IN PHARMACOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Shan Liu, Wen-Jia Kang, Anna Abrimian, Jin Xu, Luca Cartegni, Susruta Majumdar, Patrick Hesketh, Alex Bekker, Ying-Xian Pan
Summary: The OPRM1 gene undergoes extensive alternative splicing to produce multiple splice variants with important pharmacological implications for the actions of opioid drugs. These variants can mediate distinct effects of various mu opioids and be targeted for the development of novel analgesics with potent efficacy against multiple types of pain while reducing side effects associated with traditional opiates.
Article
Multidisciplinary Sciences
Ram Kandasamy, Todd M. Hillhouse, Kathryn E. Livingston, Kelsey E. Kochan, Claire Meurice, Shainnel O. Eans, Ming-Hua Li, Andrew D. White, Bernard P. Roques, Jay P. McLaughlin, Susan L. Ingram, Neil T. Burford, Andrew Alt, John R. Traynor
Summary: Positive allosteric modulators (PAMs) of the mu-opioid receptor (MOR) have been suggested as potentially safer analgesics compared to traditional opioid drugs, enhancing the activity of endogenous opioid peptides while reducing side effects. Experimental evidence shows that a specific mu-PAM, BMS-986122, can enhance the potency of endogenous opioid peptides and produce antinociceptive effects in mouse models of acute and inflammatory pain. This innovative approach to pain management may offer a safer alternative to conventional opioid medications.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Biochemistry & Molecular Biology
Hongguang Ma, Mengchu Li, Piyusha P. Pagare, Huiqun Wang, Nima Nassehi, Edna J. Santos, S. Stevens Negus, Dana E. Selley, Yan Zhang
Summary: This study synthesized a series of bivalent ligands to investigate the functional interactions between opioid and chemokine receptors. Compound 1a showed promising antinociceptive effect and may serve as a novel chemical probe for developing more potent bivalent ligands for chronic pain management.
BIOORGANIC CHEMISTRY
(2022)
Review
Pharmacology & Pharmacy
Eamonn Kelly, Alexandra Conibear, Graeme Henderson
Summary: In ligand bias, different agonist drugs activate distinct signaling pathways, leading to different therapeutic and adverse effects. While it was believed that selectively activating the G protein-dependent pathway of the mu-opioid receptor would result in effective analgesia without adverse effects, recent data suggest that most effects are mediated by this pathway and some drugs described as biased may actually be low-intrinsic-efficacy agonists. This review discusses the current understanding of bias at the mu-opioid receptor and other opioid receptor subtypes.
ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Edward L. Stahl, Laura M. Bohn
Summary: A recent study suggests that low intrinsic efficacy, rather than biased agonism, is responsible for the improvement in the separation of potency in opioid-induced respiratory suppression versus antinociception. However, reanalysis of the data presented in the study supports the conclusion that biased agonism, favoring G protein signaling, was observed. The findings provide strong evidence that G protein signaling bias can improve opioid analgesia while avoiding certain undesirable side effects.
Article
Biochemistry & Molecular Biology
Agnes Acevedo-Canabal, Travis W. Grim, Cullen L. Schmid, Nina McFague, Edward L. Stahl, Nicole M. Kennedy, Thomas D. Bannister, Laura M. Bohn
Summary: Opioid analgesics such as morphine and fentanyl induce hyperactivity in mice through mu-opioid receptor (MOR). This study reveals that noncompetitive agonists at MOR can be used to suppress morphine-induced hyperactivity while enhancing antinociceptive efficacy. Moreover, the intrinsic efficacy measured at the receptor level is not directly proportional to drug efficacy in the locomotor activity assay.
Article
Multidisciplinary Sciences
Shijia Liu, Dong-Il Kim, Tae Gyu Oh, Gerald M. Pao, Jong-Hyun Kim, Richard D. Palmiter, Matthew R. Banghart, Kuo-Fen Lee, Ronald M. Evans, Sung Han
Summary: Neurons expressing the mu-opioid receptor within the lateral parabrachial nucleus play a crucial role in opioid-induced respiratory depression (OIRD). Chemogenetic modulation of these neurons can rescue respiratory rhythms and serve as a potential therapeutic target for treating OIRD in patients.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Review
Biochemistry & Molecular Biology
Wolfgang Sadee, John C. McKew
Summary: Many G-protein-coupled receptors exhibit ligand-free basal signaling and may have physiological functions. The mu opioid receptor signals in a ligand-free form, affecting opioid drug responses. Opioid pain therapy is effective but carries adverse effects and risk of opioid use disorder. Sustained exposure to opioid agonists increases basal receptor activity, which could contribute to opioid use disorder. A neutral antagonist, 6 beta-naltrexol, can prevent opioid dependence in rodents without blocking analgesia or causing withdrawal. It could be a new therapeutic option for opioid use disorder.
Review
Pharmacology & Pharmacy
Sara Marsango, Natasja Barki, Laura Jenkins, Andrew B. Tobin, Graeme Milligan
Summary: This article discusses the physiological and pathological expression profile of GPR84 and the recent developments and use of pharmacological tool compounds to study its broader role and biology.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Article
Pharmacology & Pharmacy
Jamie J. Manning, Gabriel Rawcliffe, David B. Finlay, Michelle Glass
Summary: This study investigated the impact of phosphorylation modifications in a specific sequence of the CB1 receptor C-terminus on the translocation of Arrestin-2 and Arrestin-3. The results showed that these modifications partially contributed to the translocation of Arrestin, but complete inhibition was only achieved when all phosphorylation sites were mutated. Additionally, the dissociation of G proteins was also impaired proportionally to the extent of Arrestin translocation.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Article
Multidisciplinary Sciences
Zhaotong Cong, Fulai Zhou, Chao Zhang, Xinyu Zou, Huibing Zhang, Yuzhe Wang, Qingtong Zhou, Xiaoqing Cai, Qiaofeng Liu, Jie Li, Lijun Shao, Chunyou Mao, Xi Wang, Jihong Wu, Tian Xia, Li-Hua Zhao, Hualiang Jiang, Yan Zhang, H. Eric Xu, Xi Cheng, Dehua Yang, Ming-Wei Wang
Summary: The study found that a splice variant (SV1) of the human growth hormone-releasing hormone receptor is capable of transducing biased signal, selectively coupling to beta-arrestins while the main receptor activates Gs. Differences at the receptor N terminus lead to distinct downstream signaling pathways for GHRHR and SV1, with GHRHR predominantly activating Gs and SV1 selectively coupling to beta-arrestins.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Chemistry, Medicinal
Taryn Bosquez-Berger, Jessica A. Gudorf, Charles P. Kuntz, Jacob A. Desmond, Jonathan P. Schlebach, Michael S. VanNieuwenhze, Alex Straiker
Summary: The US is facing a severe increase in fatal drug overdoses, with synthetic opioids like fentanyl causing 80% of deaths. Naloxone, the only antidote for opiate overdose, struggles against these synthetic opioids. A study has found that (-)-Cannabidiol ((-)-CBD), a candidate negative allosteric modulator (NAM) for the mu opioid receptor, shows potential as a more potent NAM than naloxone. The study suggests that CBD analogs have potential for the development of next-generation antidotes for opioid overdose.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Biochemistry & Molecular Biology
Tao Che, Bryan L. Roth
Summary: Opioids like morphine and oxycodone are commonly used for pain relief, but they come with high abuse potential and fatal side effects. Efforts to find safer nonopioid analgesics targeting the mu-opioid receptor are facing challenges, but advancements in understanding receptor activation and signaling are leading to the discovery of alternative strategies and targets.
ANNUAL REVIEW OF BIOCHEMISTRY, VOL 90, 2021
(2021)