Article
Biochemistry & Molecular Biology
George Amato, Vineetha Vasukuttan, Danni Harris, Lucas Laudermilk, Jennifer Lucitti, Scott Runyon, Rangan Maitra
Summary: Partial agonists targeting peripheral cannabinoid receptors have potential therapeutic applications in various medical conditions. In this study, a novel compound that is a partial agonist of the human CB1 receptor with reduced brain exposure was identified.
Article
Pharmacology & Pharmacy
Vishakh Iyer, Claudia Rangel-Barajas, Taylor J. Woodward, Abhijit Kulkarni, Lucas Cantwell, Jonathon D. Crystal, Ken Mackie, George V. Rebec, Ganesh A. Thakur, Andrea G. Hohmann
Summary: Researchers have developed a novel drug candidate that can block the rewarding effects of opioid drugs by attenuating the signaling of cannabinoid type 1 (CB1) receptors. This drug works by decreasing the affinity and/or efficacy of CB1 ligands. The results show that this drug could potentially be used to prevent opioid reward and treat opioid abuse without unwanted side effects.
PHARMACOLOGICAL RESEARCH
(2022)
Article
Multidisciplinary Sciences
Ayat Zagzoog, Asher L. Brandt, Tallan Black, Eunhyun D. Kim, Riley Burkart, Mikin Patel, Zhiyun Jin, Maria Nikolaeva, Robert B. Laprairie
Summary: This study assessed select SCRAs recently identified as potential CB1R and CB2R agonists, finding several SCRAs displaying high bias for cAMP inhibition or beta arrestin2 recruitment and receptor subtype selectivity between CB1R and CB2R.
SCIENTIFIC REPORTS
(2021)
Article
Biochemistry & Molecular Biology
Thuy Nguyen, Thomas F. Gamage, Ann M. Decker, David B. Finlay, Tiffany L. Langston, Daniel Barrus, Michelle Glass, Danni L. Harris, Yanan Zhang
Summary: The research found that two CB1 negative allosteric modulators have similar structural and activity relationships, and designed a new scaffold that retains key binding features in molecular docking studies. The new hybrids showed comparable potencies to existing negative allosteric modulators in experiments.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
Article
Neurosciences
Catharine A. Mielnik, Kim S. Sugamori, David B. Finlay, Hayley H. A. Thorpe, Matthieu Schapira, Nirunthan Sivananthan, Chun Kit Li, Vincent M. Lam, Sean Harrington, Mostafa H. Abdelrahman, Laurent A. Trembleau, W. McIntyre Burnham, Jibran Y. Khokhar, Ali Salahpour, Amy J. Ramsey, Michelle Glass, Iain R. Greig, Ruth A. Ross
Summary: The endocannabinoid system plays a significant role in various psychiatric disorders, including schizophrenia. A CB1 receptor allosteric modulator, ABM300, has shown the ability to reduce behavioral deficits in transgenic models, particularly those with hyperdopaminergia.
NEUROPSYCHOPHARMACOLOGY
(2021)
Article
Pharmacology & Pharmacy
Liang Yang, Xiao Zhu, David B. Finlay, Hayley Green, Michelle Glass, Stephen B. Duffull
Summary: A unified mathematical model was developed to describe the allosteric modulation of CB1 receptor. A hypothetical transitional state, CP55940-CB1-Org27569, was identified as the key factor in explaining the modulation effect of Org27569. This model reveals a novel mechanism of allosteric modulation.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Article
Chemistry, Medicinal
Sumanta Garai, Luciana M. Leo, Anna-Maria Szczesniak, Dow P. Hurst, Peter C. Schaffer, Ayat Zagzoog, Tallan Black, Jeffrey R. Deschamps, Elke Miess, Stefan Schulz, David R. Janero, Alex Straiker, Roger G. Pertwee, Mary E. Abood, Melanie E. M. Kelly, Patricia H. Reggio, Robert B. Laprairie, Ganesh A. Thakur
Summary: By introducing a methyl group at the a-position of the nitro group, the greater potency and efficacy of the 2-phenylindole-based cannabinoid type-1 receptor (CB1R) agonist-positive allosteric modulator was achieved, offering safer therapeutic candidates for glaucoma and potentially other diseases. The diastereoselective CB1R-allosteric modulator interaction was demonstrated for the first time, with one enantiomer showing improved potency and the other biased towards specific signaling pathways. Exploiting G-protein biased CB1R-allosteric modulation shows promise for developing more effective and targeted treatments.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Oscar Diaz, Pedro Renault, Jesus Giraldo
Summary: Using molecular dynamics simulations, the structural effect of the F237L mutation on CB1 was examined. The mutation had a global impact on CB1 conformations, hindering TM6 outward movement and the conformational change of the NPxxY motif upon activation by CP55940. CP55940 interactions with CB1 within the orthosteric binding site were altered. These findings suggest that the mutation site is a key region for allosteric modulation in CB1.
Article
Biochemistry & Molecular Biology
Xinfei Wei, Wanqiu Huang, Mengjing Teng, Hao Shen, Bin Feng, Liangqiang Chen, Fan Yang, Li Wang, Shaoning Yu
Summary: The study systematically investigated the conformational changes in α-amylase induced by different ligands including metal ions, substrates, and aromatic compounds in liquor production. The results showed that interactions with active metal cations increased the exposure of active sites in α-amylase, while interactions with substrates reduced the degree of exposure and made the enzyme more rigid and compact. Inhibitory metal cations and aromatic compounds increased the exposure of active sites but reduced the enzymatic activity. These findings provide valuable insights for controlling conditions and improving production efficiency.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2023)
Article
Biochemistry & Molecular Biology
Jakub Jakowiecki, Renata Abel, Urszula Orzel, Pawel Pasznik, Robert Preissner, Slawomir Filipek
Summary: The N-terminal domain of the CB1 cannabinoid receptor is crucial for the allosteric binding of cannabidiol (CBD) and plays a key role in the stable binding of CBD in the allosteric site. The presence of the complete N-terminal domain is also essential for the allosteric-orthosteric coupling mechanism of CBD in modulating the CB1R.
Article
Biochemistry & Molecular Biology
Michal Gala, Peter Pristas, Gabriel Zoldak
Summary: This paper examined the impact of opening and formation of subdomain interfaces during the evolution of Heat shock proteins 70 (Hsp70). It found that indel events, such as insertions and deletions, in specific regions disrupt the mechanical balance of the protein and cause dysfunction. The study highlights the importance of considering the balance between structural elements in the rational design of functional allosteric machines.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Pharmacology & Pharmacy
David B. Finlay, Thuy Nguyen, Thomas F. Gamage, Shuli Chen, Daniel G. Barrus, Purvi R. Patel, Brian F. Thomas, Jenny L. Wiley, Yanan Zhang, Michelle Glass
Summary: This study compared the synthetic cannabinoid receptor agonist EG-018 and its analogues with existing putative neutral antagonists of CB1 receptor. The results showed highly variable signaling outcomes for EG-018 analogues, with some compounds demonstrating potential as neutral antagonists. These findings provide important insights for the development of CB1 neutral antagonists.
PHARMACOLOGY RESEARCH & PERSPECTIVES
(2022)
Article
Biophysics
Christopher Pfleger, Jana Kusch, Mahesh Kondapuram, Tina Schwabe, Christian Sattler, Klaus Benndorf, Holger Gohlke
Summary: The opening of HCN channels is controlled by membrane hyperpolarization and the binding of cyclic nucleotides to the CNBD domain. Through a rigidity-theory-based approach, researchers identified different pathways within the CL-CNBD that modulate cAMP-binding responses. Results suggest the presence of functionally relevant submodules within and across structurally discernible subunits in HCN channels.
BIOPHYSICAL JOURNAL
(2021)
Article
Pharmacology & Pharmacy
Luis Gustavo A. Patrone, Gustavo D. D. Ferrari, Rodrigo Moreira da Silva, Luciane C. C. Alberici, Norberto Peporine Lopes, Angelita M. M. Stabile, Wilfried Klein, Kenia C. Bicego, Luciane H. H. Gargaglioni
Summary: Cannabis legalization has led to increased cannabis use during pregnancy. This study found that prenatal exposure to synthetic cannabinoid WIN can affect the respiratory control system of neonatal and juvenile rats, with greater CO2 sensitivity in males and breathing and brainstem changes. In females, it leads to increased apnea and reduced serotonin neurons. These findings demonstrate long-term and sex-specific consequences of excessive stimulation of the endocannabinoid system during gestation.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Diego A. Rodriguez-Soacha, Sophie A. M. Steinmueller, Ali Isbilir, Julia Fender, Marie H. Deventer, Yesid A. Ramirez, Anna Tutov, Christoph Sotriffer, Christophe P. Stove, Kristina Lorenz, Martin J. Lohse, James N. Hislop, Michael Decker
Summary: This study synthesized new agonist ligands for hCB1R through the design of different classes of photoswitchable molecules, evaluated their mechanisms of action and pharmacological properties through various experimental methods, providing a new molecular tool for studying the role of cannabinoid receptors in related diseases.
ACS CHEMICAL NEUROSCIENCE
(2022)