Article
Pharmacology & Pharmacy
Anindya Ghosh, Marie-Line Peyot, Yat Hei Leung, Francois Ravenelle, S. R. Murthy Madiraju, Marc Prentki
Summary: MRI-1891, a peripherally restricted CB1R inverse agonist, enhances glucose stimulated insulin secretion in isolated human and mouse pancreatic islets, and protects islet cells from cytokine-induced apoptosis, showing potential as a therapeutic for both type 1 and type 2 diabetes.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2023)
Article
Chemistry, Multidisciplinary
Shira Hirsch, Liad Hinden, Meital Ben -David Naim, Saja Baraghithy, Anna Permyakova, Shahar Azar, Taher Nasser, Emma Portnoy, Majd Agbaria, Alina Nemirovski, Gershon Golomb, Joseph Tam
Summary: The overactivation of the endocannabinoid/CB1R system is a key feature of obesity and its related diseases. However, the use of drugs to block CB1R has been limited by their adverse effects. In this study, a nanotechnology-based drug delivery system was developed to encapsulate a CB1R antagonist for targeted treatment of obesity-related diseases.
JOURNAL OF CONTROLLED RELEASE
(2023)
Article
Biochemistry & Molecular Biology
Tania Muller, Laurent Demizieux, Stephanie Troy-Fioramonti, Chloe Buch, Julia Leemput, Christine Belloir, Jean-Paul Pais De Barros, Tony Jourdan, Patricia Passilly-Degrace, Xavier Fioramonti, Anne-Marie Le Bon, Bruno Verges, Jean-Michel Robert, Pascal Degrace
Summary: JM-00266, a peripherally restricted CB1 receptor blocker, shows promising effects in improving metabolic disorders associated with obesity. It exhibits inverse agonist activity on CB1 receptors, counteracts anandamide-induced gastroparesis, and improves glucose tolerance and insulin sensitivity in wild-type mice.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Pharmacology & Pharmacy
Hebatallah M. Hussein, Mohammed F. Elyamany, Laila A. Rashed, Nada A. Sallam
Summary: The study shows that vitamin D plays a significant role in improving gut dysbiosis and gut barrier dysfunction induced by high-fat, high-sucrose diet/streptozotocin, and it can also suppress metabolic disorders and cognitive dysfunction associated with diabetes. Vitamin D reduces inflammation levels by regulating colonic CB1R and increasing the expression of tight junction proteins ZO-1 and occludin, leading to improved glycemic control and cognitive function.
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
(2022)
Article
Chemistry, Multidisciplinary
Sophie A. M. Steinmueller, Julia Fender, Marie H. H. Deventer, Anna Tutov, Kristina Lorenz, Christophe P. P. Stove, James N. N. Hislop, Michael Decker
Summary: In this study, a photoswitchable scaffold based on the privileged structure of benzimidazole was designed and synthesized for CB2R efficacy-switch. Compound 10d, a trans-on agonist, was developed and used as a molecular probe to investigate the mechanisms of CB2R-βarr2 dependent endocytosis. This is the first light-dependent functionally selective agonist for studying the complex mechanisms of CB2R-βarr2 pathway.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Biochemistry & Molecular Biology
Sarah A. Hindson, Rachael C. Andrews, Michael J. Danson, Marc W. van Der Kamp, Amy E. Manley, Oliver B. Sutcliffe, Tom S. F. Haines, Tom P. Freeman, Jennifer Scott, Stephen M. Husbands, Ian S. Blagbrough, J. L. Ross Anderson, David R. Carbery, Christopher R. Pudney
Summary: Synthetic cannabinoid receptor agonists (SCRAs) are rapidly growing recreational drugs with diverse effects and severe side effects. This study hypothesized that SCRAs may act as monoamine oxidase inhibitors (MAOIs) based on their structural similarity and matching clinical outcomes. Through in silico and experimental studies, it was found that SCRAs are MAO-A-specific inhibitors and their affinity varies depending on the nature of the SCRA 'head' group. This research indicates that SCRA activity is not limited to cannabinoid receptor agonism and suggests alternative interactions to explain their diverse side effects.
Article
Chemistry, Multidisciplinary
Amer H. Tarawneh, Pankaj Pandey, Lo'ay A. Al-Momani, Anastassiya Gadetskaya, Sultan T. Abu-Orabi, Robert J. Doerksen, Stephen J. Cutler
Summary: The CB2 receptor, as a potential target for treating various neuroinflammatory or neurodegenerative diseases, has attracted significant interest, and the search for new compounds as highly selective CB2 modulators is of great importance.
ARABIAN JOURNAL OF CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Yaliang Tang, Barbara Wolk, Ryan Nolan, Caitlin E. Scott, Debra A. Kendall
Summary: Testing four ABK5 derivatives revealed that ABK5-1 and ABK5-2 have higher affinity and efficacy as CB2-selective agonists, while maintaining subtype selectivity. These compounds showed potential for treating inflammation with stronger effects observed in ABK5-1.
Article
Neurosciences
Yingying Han, Qianyu Dong, Jiyun Peng, Baoming Li, Chong Sun, Chaolin Ma
Summary: Cannabis, a plant with a long history of medical use, can cause various side effects when abused. Research suggests that cannabinoid receptors, particularly CB1R, are widely distributed in the central nervous system and play a role in mental disorders. This study found that CB1R is highly expressed in the prefrontal cortex of nonhuman primates, particularly in area 46, and its abnormal expression may be related to cannabis-induced side effects.
MOLECULAR NEUROBIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Douglas L. Orsi, Steven J. Ferrara, Stephan Siegel, Anders Friberg, Lea Bouche, Elisabeth Pook, Philip Lienau, Joseph P. Bluck, Christopher T. Lemke, Gizem Akcay, Timo Stellfeld, Hanna Meyer, Vera Puetter, Simon J. Holton, Daniel Korr, Isabel Jerchel-Furau, Constantia Pantelidou, Craig A. Strathdee, Matthew Meyerson, Knut Eis, Jonathan T. Goldstein
Summary: PPAR gamma (PPARG) is a ligand activated transcription factor that regulates genes involved in various biological processes. Inverse agonists of PPARG offer a potential avenue to modulate PPARG biology in vivo, but current inverse agonists lack favorable in vivo properties. The discovery and characterization of a series of orally bioavailable 4-chloro-6-fluoroisophthalamides as covalent PPARG inverse-agonists provide new tools for future studies to explore their potential utility for treatment of disorders related to hyperactivated PPARG.
BIOORGANIC & MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Zhipei Gao, Yongli Du, Xiehuang Sheng, Jingkang Shen
Summary: ERRα inverse agonists are effective in inhibiting the migration and invasion of cancer cells, and the total binding free energy is positively correlated with their biological activity. The interaction of inverse agonists with the hydrophobic interlayer composed of Phe328 and Phe495 plays a crucial role in determining their biological activity.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Chemistry, Multidisciplinary
Yi Zhao, Ying Wang, Huibin Wang, Baichun Hu, Zhaohu Luo, Fengjiao Zhang
Summary: The study revealed the structural differences between CB1 and CB2 receptors, highlighting the importance of binding pocket shape in determining ligand selectivity. Strategies to improve selectivity towards CB2, such as increasing molecular size and optimizing hydrogen bond interactions, were proposed based on the key residues that determine receptor selectivity. This information provides a promising foundation for the future design of selective inhibitors targeting CB2.
NEW JOURNAL OF CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Francesca Gado, Rebecca Ferrisi, Sarah Di Somma, Fabiana Napolitano, Kawthar A. Mohamed, Lesley A. Stevenson, Simona Rapposelli, Giuseppe Saccomanni, Giuseppe Portella, Roger G. Pertwee, Robert B. Laprairie, Anna Maria Malfitano, Clementina Manera
Summary: This study synthesized and characterized new 1,8-naphthyridin-2(1H)-one-3-carboxamides with high affinity and selectivity for CB2R. These compounds showed anticancer activity by modulating the cAMP response and modulating ERK1/2 expression through a CB2R-mediated mechanism.
Article
Chemistry, Multidisciplinary
Sameek Singh, Ian Liddle, Christa Macdonald, Joel D. A. Tyndall, Michelle Glass, Andrea J. Vernall
Summary: CB2R is an important therapeutic target for pain and inflammatory disorders, and better understanding of GPCR location requires tools that can differentiate cell surface versus subcellular receptors.
AUSTRALIAN JOURNAL OF CHEMISTRY
(2021)
Article
Cell Biology
Monica Patel, David B. Finlay, Michelle Glass
Summary: SCRAs were originally developed to explore therapeutic benefits of cannabinoid receptor activation, but have been diverted to the recreational drug market, potentially leading to toxicity. Biased agonists can maximize drug effectiveness by reducing adverse effects, but the signaling pathways of cannabinoid receptors are still unclear.
CELLULAR SIGNALLING
(2021)