Article
Chemistry, Medicinal
Ying-Ting Hsu, Shen-Ren Chen, Yung-Chiao Chang, Hsiao-Fu Chang, Teng-Kuang Yeh, Jian-Ying Chuang, Horace H. Loh, Hsing-Pang Hsieh, Shau-Hua Ueng, Shiu-Hwa Yeh
Summary: The demand for a non-addictive analgesic medication is increasing due to clinical misuse. Compound 14 is a dual agonist of the mu opioid receptor (MOR) and nociceptin-orphanin FQ opioid peptide (NOP) receptor, providing pain relief at very small doses and reducing unwanted side effects. Evaluating its effects in wild type and humanized mice can help develop a safer prescription analgesic drug.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Maree T. Smith, Dehui Kong, Andy Kuo, Mohammad Z. Imam, Craig M. Williams
Summary: This article discusses the limitations and problems associated with strong opioid analgesics and describes international efforts to discover new and safer opioids. It focuses on medicinal chemistry strategies using structurally diverse compounds derived from natural sources as lead molecules and elaborates on the current research status and approaches in the discovery of novel opioid ligands that retain analgesic effects with improved safety and reduced adverse effects, particularly addiction liability.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Pharmacology & Pharmacy
Karan H. Muchhala, Joanna C. Jacob, William L. Dewey, Hamid Akbarali
Summary: The role of 0-arrestin-2 in opioid tolerance was investigated, showing its involvement in acute, but not chronic tolerance in dorsal root ganglia neurons and in vivo antinociception. These findings suggest that opioid-induced antinociceptive tolerance can develop even without 0-arrestin-2 activation, significantly impacting the clinical utility of biased agonists.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2021)
Article
Chemistry, Medicinal
Maree T. Smith, Dehui Kong, Andy Kuo, Mohammad Z. Imam, Craig M. Williams
Summary: The opioid crisis has increased the demand for novel opioid analgesics that have superior profiles compared to morphine. This Perspective reviews and discusses the multitargeted opioid ligand strategy for discovering such analgesics. Dual-targeted mu-opioid/delta-opioid (MOP/DOP) ligands with strong DOP antagonist potency and without DOP or kappa-opioid (KOP) agonist activity are promising candidates. Dual-targeted MOP/NOP partial agonists also show potential. The pharmacologic template of cebranopadol, a full agonist at MOP, DOP, and NOP receptors, and a partial agonist at KOP receptor, should be avoided due to its poor therapeutic indices.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Pharmacology & Pharmacy
Alba Vidal-Torres, Begona Fernandez-Pastor, Monica Garcia, Eva Ayet, Anna Cabot, Javier Burgueno, Xavier Monroy, Bertrand Aubel, Xavier Codony, Luz Romero, Rosalia Pascual, Maria Teresa Serafini, Gregorio Encina, Carmen Almansa, Daniel Zamanillo, Manuel Merlos, Jose Miguel Vela
Summary: WLB-73502 is a dual compound that binds sigma-1 (S1R) and mu-opioid (MOR) receptors. It exhibits analgesic efficacy with a better safety profile compared to strong opioids.
ACTA PHARMACEUTICA SINICA B
(2023)
Article
Biochemistry & Molecular Biology
R. Bruno Hernandez-Alvarado, Abraham Madariaga-Mazon, Fernando Cosme-Vela, Andres F. Marmolejo-Valencia, Adel Nefzi, Karina Martinez-Mayorga
Summary: By conducting molecular dynamics simulations of two biased ligands and a reference molecule, a protein-ligand interaction fingerprint distinguishing biased ligands was identified. Virtual screening of a database containing 68,740 ligands highlighted exemplary molecules with biased agonism, showcasing the utility of this approach in searching for biased MOR ligands and enhancing understanding of MOR biased signaling.
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
(2021)
Review
Chemistry, Medicinal
Tao Zhuang, Jiaying Xiong, Shuaishuai Hao, Wei Du, Zhenming Liu, Bifeng Liu, Guisen Zhang, Yin Chen
Summary: Opioid analgesics are effective for pain management but have undesirable side effects, prompting the need for new, safer analgesics. The sigma-1 receptor plays a crucial role in pain modulation and its antagonists can reduce pain and enhance the effects of opioid analgesics.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Ramajayam Kuppusamy, Ying-Ting Hsu, Yi-Yu Ke, Po-Wei Chang, Yung-Chiao Chang, Hsiao-Fu Chang, Pei-Chen Wang, Yu-Hao Lin, Yu-Chen Huang, Teng-Kuang Yeh, Jian-Ying Chuang, Horace H. Loh, Chuan Shih, Chiung-Tong Chen, Shiu-Hwa Yeh, Shau-Hua Ueng
Summary: This study modified the structure of a previously identified compound and discovered a new, potent analgesic with reduced side effects. The analgesic activated mu-opioid receptors through specific signaling pathways and showed weak effects on other related receptors. It exhibited strong antinociception in pain and allodynia models with less gastrointestinal inhibition and tolerance compared to morphine.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
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)
Article
Pharmacology & Pharmacy
Alexander R. French, Richard M. van Rijn
Summary: Kappa opioid receptor (icOR) agonists are considered safer alternatives to clinically used mu opioid receptor (mu OR) analgesics with no abuse liability and respiratory depression effects. However, they have their own limiting adverse effects that hinder clinical translation. Recent studies suggest that these effects may be due to distinct intracellular signaling pathways, leading to the hypothesis that biased icOR agonists away from ll-arrestin signaling could have improved therapeutic windows. Overall, G-protein-biased icOR agonists generally have better therapeutic windows compared to unbiased agonists, although study design limits strong conclusions in this regard. The development of biased icOR agonists and new tools in the field puts icOR research in a position to advance our understanding and translation of biased icOR agonists to clinical use.
PHARMACOLOGICAL RESEARCH
(2022)
Article
Neurosciences
Edel M. Hughes, Patricia Calcagno, Connie Sanchez, Karen Smith, John P. Kelly, David P. Finn, Michelle Roche
Summary: This study found differential effects of acute morphine administration on social behavior and immediate early gene expression in rats prenatally exposed to VPA compared to saline-exposed controls. Morphine had a smaller impact on sociability and social novelty preference behavior in VPA-exposed rats but affected immediate early gene expression in the hippocampus.
BRAIN RESEARCH BULLETIN
(2021)
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
Biochemistry & Molecular Biology
Charlene Gadais, Justyna Piekielna-Ciesielska, Jolien De Neve, Charlotte Martin, Anna Janecka, Steven Ballet
Summary: Opioid agonists are commonly used for pain relief, but their side effects can be problematic. Designed multiple ligands (DMLs) offer a promising approach by targeting both opioid and non-opioid pathways involved in pain perception. Newly designed opioid agonist-NK2 or -NK3 antagonists show potential for future opioid hybrid development.
Article
Pharmacology & Pharmacy
Edna J. Santos, Matthew L. Banks, S. Stevens Negus
Summary: The degree of mu opioid receptor (MOR) efficacy required to produce hyperactivity in mice was evaluated in this study. The results showed that the hyperactivity induced by MOR agonists is efficacy dependent and requires relatively high levels of MOR agonist efficacy for its full expression.
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
(2022)
Article
Clinical Neurology
Neel Mehta, Neal E. Slatkin, Robert J. Israel, Nancy Stambler, Eric D. Shah
Summary: This study evaluated the safety and efficacy of methylnaltrexone in constipated patients and found that methylnaltrexone significantly improved rescue-free laxation. Abdominal pain was more common in patients receiving methylnaltrexone.
JOURNAL OF PAIN RESEARCH
(2023)
Review
Biochemistry & Molecular Biology
Samuel T. Slocum, Jeffrey F. DiBerto, Bryan L. Roth
Summary: A confluence of factors has reignited interest in psychedelic drugs, with the FDA designating psilocybin as a Breakthrough Therapy for treatment-resistant depression. The clearer understanding of how these drugs exert their effects at the molecular level is essential for further development of applications in hallucinogenic and therapeutic mechanisms.
JOURNAL OF NEUROCHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Wesley B. Asher, Daniel S. Terry, G. Glenn A. Gregorio, Alem W. Kahsai, Alessandro Borgia, Bing Xie, Arnab Modak, Ying Zhu, Wonjo Jang, Alekhya Govindaraju, Li-Yin Huang, Asuka Inoue, Nevin A. Lambert, Vsevolod V. Gurevich, Lei Shi, Robert J. Lefkowitz, Scott C. Blanchard, Jonathan A. Javitch
Summary: Beta-arrestins are strongly autoinhibited in their basal state but can be activated by phosphorylated receptors and receptor agonism, releasing the beta-arrestin tail and allowing it to assume different conformations. The rate and efficiency of beta-arrestin activation depend on the phosphorylation pattern of the receptor and agonist-promoted receptor activation.
Editorial Material
Biochemistry & Molecular Biology
Richard M. van Rijn, Mariana Spetea
Article
Pharmacology & Pharmacy
Alexander R. French, Richard M. van Rijn
Summary: Kappa opioid receptor (icOR) agonists are considered safer alternatives to clinically used mu opioid receptor (mu OR) analgesics with no abuse liability and respiratory depression effects. However, they have their own limiting adverse effects that hinder clinical translation. Recent studies suggest that these effects may be due to distinct intracellular signaling pathways, leading to the hypothesis that biased icOR agonists away from ll-arrestin signaling could have improved therapeutic windows. Overall, G-protein-biased icOR agonists generally have better therapeutic windows compared to unbiased agonists, although study design limits strong conclusions in this regard. The development of biased icOR agonists and new tools in the field puts icOR research in a position to advance our understanding and translation of biased icOR agonists to clinical use.
PHARMACOLOGICAL RESEARCH
(2022)
Article
Behavioral Sciences
Alexander R. French, Anna M. Gutridge, Jinling Yuan, Q. Hawk Royer, Richard M. van Rijn
Summary: The study revealed that agonists with high efficacy for recruiting beta-arrestin 2 by the kappa opioid receptor are less effective in modulating ethanol consumption compared to agonists with low efficacy. However, reducing beta-arrestin 2 levels amplified the ethanol consumption-promoting effects of kappa agonists. Overall, there appears to be a complex relationship between agonist profile, gender, and kappa opioid receptor modulation of ethanol consumption.
PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR
(2022)
Article
Pharmacology & Pharmacy
Arryn T. Blaine, Yiming Miao, Jinling Yuan, Sophia Palant, Rebecca J. J. Liu, Zhong-Yin Zhang, Richard. M. van Rijn
Summary: The study found that beta-arrestin 2 is positively correlated with the intensity of delta OR agonist-induced seizures, but global beta-arrestin 1 knockout mice are not an ideal model system to investigate their mechanism of action.
FRONTIERS IN PHARMACOLOGY
(2022)
Review
Chemistry, Medicinal
Yazan J. Meqbil, Richard M. van Rijn
Summary: The delta opioid receptor is a GPCR with broad expression patterns and potential for treating various diseases, but specific molecules targeting it have not yet reached clinical translation. Novel ligands need to be identified for clinical trials and there are opportunities for in silico drug discovery at the delta opioid receptor to find modulators with unique pharmacological properties.
Article
Biochemistry & Molecular Biology
Luke L. Liu, Richard M. van Rijn, Wei Zheng
Summary: The subventricular zone in the adult brain contains high amounts of copper, which is linked to the stability of adult neurogenesis in this region. This study shows that chelating copper ions using a copper chelator can reduce copper levels in the subventricular zone and enhance the differentiation and migration of neural stem/progenitor cells.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Multidisciplinary Sciences
Abdelfattah Faouzi, Haoqing Wang, Saheem A. Zaidi, Jeffrey F. DiBerto, Tao Che, Qianhui Qu, Michael J. Robertson, Manish K. Madasu, Amal El Daibani, Balazs R. Varga, Tiffany Zhang, Claudia Ruiz, Shan Liu, Jin Xu, Kevin Appourchaux, Samuel T. Slocum, Shainnel O. Eans, Michael D. Cameron, Ream Al-Hasani, Ying Xian Pan, Bryan L. Roth, Jay P. McLaughlin, Georgios Skiniotis, Vsevolod Katritch, Brian K. Kobilka, Susruta Majumdar
Summary: Researchers have developed a new approach to design safer therapeutic agents by targeting a conserved sodium ion-binding site in mu-opioid receptors. Cryo-electron microscopy structures revealed the key interactions between the ligands and the binding site, leading to the development of potent ligands with reduced adverse effects. This study highlights the potential of targeting the sodium ion-binding site for the design of safer analgesics and suggests that engagement of this site can control the efficacy and selectivity profiles of G-protein-coupled receptors.
Article
Chemistry, Medicinal
Madeline R. Hennessy, Anna M. Gutridge, Alexander R. French, Elizabeth S. Rhoda, Yazan J. Meqbil, Meghna Gill, Yavnika Kashyap, Kevin Appourchaux, Barnali Paul, Zaijie Jim Wang, Richard M. van Rijn, Andrew P. Riley
Summary: Akuammine and pseudoakuammigine are indole alkaloids derived from the seeds of the akuamma tree. They act as weak agonists of the mu opioid receptor and show minimal effects in animal models of antinociception. By synthesizing 22 semisynthetic derivatives and evaluating their activity at the mu opioid receptor and kappa opioid receptor, we identified derivatives with improved potency at the mu opioid receptor.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Natalie Hewitt, Ning Ma, Nadia Arang, Sarah A. Martin, Ajit Prakash, Jeffrey F. DiBerto, Kevin M. Knight, Soumadwip Ghosh, Reid H. J. Olsen, Bryan L. Roth, J. Silvio Gutkind, Nagarajan Vaidehi, Sharon L. Campbell, Henrik G. Dohlman
Summary: Heterotrimeric guanine nucleotide-binding proteins (G proteins) act as molecular switches for cellular growth and metabolism. Mutations in the glutamine residue critical for GTP hydrolysis in the G protein alpha subunit are common in uveal melanoma. Our study reveals that these mutations have functional diversity and contribute to G protein functions beyond GTP hydrolysis.
Article
Multidisciplinary Sciences
Amal El Daibani, Joseph M. M. Paggi, Kuglae Kim, Yianni D. D. Laloudakis, Petr D. Popov, Sarah M. M. Bernhard, Brian E. E. Krumm, Reid H. J. Olsen, Jeffrey Diberto, F. Ivy Carroll, Vsevolod Katritch, Bernhard Wuensch, Ron O. O. Dror, Tao Che
Summary: Using structural determination, molecular dynamics simulations, and functional assays, the researchers identified molecular determinants of KOR signaling bias. They determined the crystal structure of KOR bound to the G protein-biased agonist nalfurafine and identified an arrestin-biased KOR agonist, WMS-X600. Through simulations and mutagenesis validation, they explained how agonists achieve biased signaling at KOR.
NATURE COMMUNICATIONS
(2023)
Article
Endocrinology & Metabolism
Jacob Emil Petersen, Maria Hauge Pedersen, Oksana Dmytriyeva, Emilie Nellemose, Tulika Arora, Maja Storm Engelstoft, Wesley B. Asher, Jonathan A. Javitch, Thue W. Schwartz, Mette Trauelsen
Summary: The activation of FFAR1 can induce both IP3/Ca2+ signaling pathway and cAMP signaling pathway, and the co-activation of these two pathways is required for the highly efficient hormone secretion induced by second-generation FFAR1 agonists. Adcy2 gene is highly expressed in enteroendocrine cells of the intestine and may mediate Gq-driven cAMP signaling response.
MOLECULAR METABOLISM
(2023)
Article
Neurosciences
Arryn T. Blaine, Richard M. van Rijn
Summary: This review provides a comprehensive overview of the current state of knowledge of 6OR agonist-mediated seizures, highlighting which agonists produce seizures, which brain regions are implicated, and which signaling mediators have been examined. The hope is that this review will inspire carefully designed studies to solve the question of why certain 6OR agonists are seizurogenic, and expedite the development of novel 6OR clinical candidates without the risk of inducing seizures.
Article
Multidisciplinary Sciences
Abdelfattah Faouzi, Haoqing Wang, Saheem A. Zaidi, Jeffrey F. DiBerto, Tao Che, Qianhui Qu, Michael J. Robertson, Manish K. Madasu, Amal El Daibani, Balazs R. Varga, Tiffany Zhang, Claudia Ruiz, Shan Liu, Jin Xu, Kevin Appourchaux, Samuel T. Slocum, Shainnel O. Eans, Michael D. Cameron, Ream Al-Hasani, Ying Xian Pan, Bryan L. Roth, Jay P. McLaughlin, Georgios Skiniotis, Vsevolod Katritch, Brian K. Kobilka, Susruta Majumdar
Summary: This study presents an approach to design safer analgesics by targeting a conserved sodium ion-binding site in mu-opioid receptor (mu OR) using bitopic fentanyl derivatives. Cryo-electron microscopy structures reveal key interactions between the ligands and mu OR, demonstrating nanomolar potency, high efficacy, and reduced adverse effects. This study suggests the potential of the mu OR sodium ion-binding site as a target for the design of safer analgesics.