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
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
Chemistry, Medicinal
Peter Obi, Senthil Natesan
Summary: An increasing number of studies have revealed novel lipid-regulated sites in the structures of G-protein-coupled receptors (GPCRs). Ligands must pass through lipid paths in the surrounding membrane to access these sites. However, the current experimental structures often overlook the contribution of surrounding lipids to ligand access and binding. In this study, molecular dynamics simulations were used to demonstrate the critical role of membrane lipids in the access and binding of ORG27569 and its analogs at the transmembrane site of the cannabinoid CB1 receptor. These findings highlight the importance of incorporating membrane lipids in accurate characterization and optimization of drugs.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Pharmacology & Pharmacy
Amina M. Bagher, Lenah S. Binmahfouz, Rasheed A. Shaik, Basma G. Eid
Summary: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of chemotherapy, and there is currently no effective pharmacological treatment available. Activating the CB1 receptor has shown promise in alleviating CIPN-related pain and neuroinflammation. This study investigated the potential benefits of a newly synthesized CB1 positive allosteric modulator, GAT229, in alleviating neuropathic pain and slowing CIPN progression.
SAUDI PHARMACEUTICAL JOURNAL
(2023)
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
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
David F. Lee, Matan Geron, Gregory Scherrer
Summary: The structural studies of a positive allosteric modulator of the adenosine A(1) receptor reveal the mechanisms by which stabilizing the GPCR-G protein complex bound to its endogenous agonist results in analgesic efficacy in an animal model of neuropathic pain.
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Daniel J. Nasrallah, Neil K. Garg
Summary: This study reports on the synthesis and characterization of two isomeric hexahydrocannabinols (HHCs), (9R)-HHC and (9S)-HHC, which are derivatives of known psychoactive cannabinoids. The researchers used hydrogen-atom transfer reduction to prepare the compounds, with (9R)-HHC being the major diastereomer. They also conducted cannabinoid receptor studies and found that (9R)-HHC has similar binding affinity and activity to Δ9-THC, while (9S)-HHC binds strongly to the receptors but displays reduced activity in functional assays. The variability in HHC isomer ratios found in commercially available products highlights the need for further research and systematic testing of new cannabinoids.
ACS CHEMICAL BIOLOGY
(2023)
Article
Pharmacology & Pharmacy
Dennis F. Lovelock, Thuy Nguyen, Kalynn Van Voorhies, Yanan Zhang, Joyce Besheer
Summary: The endocannabinoid system, specifically the CB1 receptor, plays a role in alcohol use disorder (AUD). The CB1 negative allosteric modulator RTICBM-74 reduces alcohol self-administration without impacting locomotion or sucrose self-administration in rats, suggesting its potential therapeutic value for AUD treatment.
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
(2022)
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
Chemistry, Medicinal
Thuy Nguyen, Thomas F. Gamage, David B. Finlay, Ann M. Decker, Tiffany L. Langston, Daniel Barrus, Michelle Glass, Jun-Xu Li, Terry P. Kenakin, Yanan Zhang
Summary: This study demonstrated that CB1 receptor negative allosteric modulators attenuated cocaine-seeking behaviors in rats. By introducing substituents with different properties to the phenethyl group, the potency of CB1 NAMs was evaluated. The 3-chloro analogue showed promising results in selectively attenuating cocaine-seeking behavior without affecting locomotion.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Xin Yang, Xuehui Wang, Zheng Xu, Chao Wu, Yangli Zhou, Yifei Wang, Guifeng Lin, Kan Li, Ming Wu, Anjie Xia, Jingming Liu, Lin Cheng, Jun Zou, Wei Yan, Zhenhua Shao, Shengyong Yang
Summary: This study presents the crystallographic and cryo-electron microscopy structures of CB1 receptor bound to the allosteric modulator ZCZ011. The results show that ZCZ011 induces rearrangement of TM2, promoting receptor activation and increasing the population of active receptors. In contrast, the negative allosteric modulator ORG27569 inhibits TM2 rearrangement. These findings provide insights into CB1 allosteric regulation and have implications for the rational design of allosteric modulators.
NATURE CHEMICAL BIOLOGY
(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
Multidisciplinary Sciences
Zhenhua Shao, Jie Yin, Karen Chapman, Magdalena Grzemska, Lindsay Clark, Junmei Wang, Daniel M. Rosenbaum
Article
Biochemistry & Molecular Biology
Karthik Ramesh, Dilraj Lama, Kang Wei Tan, Van Sang Nguyen, Fook Tim Chew, Chandra S. Verma, Yu Keung Mok
Article
Multidisciplinary Sciences
Van Sang Nguyen, Kang Wei Tan, Karthik Ramesh, Fook Tim Chew, Yu Keung Mok
SCIENTIFIC REPORTS
(2017)
Article
Allergy
Karthik Ramesh, Sri Anusha Matta, Fook Tim Chew, Yu Keung Mok
Article
Biochemistry & Molecular Biology
Rustam Ali, Lindsay D. Clark, Jacob A. Zahm, Andrew Lemoff, Karthik Ramesh, Daniel M. Rosenbaum, Michael K. Rosen
JOURNAL OF BIOMOLECULAR NMR
(2019)
Article
Multidisciplinary Sciences
Wei Yan, Lin Cheng, Wei Wang, Chao Wu, Xin Yang, Xiaozhe Du, Liang Ma, Shiqian Qi, Yuquan Wei, Zhiliang Lu, Shengyong Yang, Zhenhua Shao
NATURE COMMUNICATIONS
(2020)
Article
Biochemistry & Molecular Biology
Peng Xiao, Wei Yan, Lu Gou, Ya-Ni Zhong, Liangliang Kong, Chao Wu, Xin Wen, Yuan Yuan, Sheng Cao, Changxiu Qu, Xin Yang, Chuan-Cheng Yang, Anjie Xia, Zhenquan Hu, Qianqian Zhang, Yong-Hao He, Dao-Lai Zhang, Chao Zhang, Gui-Hua Hou, Huanxiang Liu, Lizhe Zhu, Ping Fu, Shengyong Yang, Daniel M. Rosenbaum, Jin-Peng Sun, Yang Du, Lei Zhang, Xiao Yu, Zhenhua Shao
Summary: Dopamine receptors, includingD1- and D2-like receptors, are key therapeutic targets in various neurological syndromes, cardiovascular, and kidney diseases. This study presents cryo-EM structures of the dopamine D1 receptor (DRD1) coupled to Gs heterotrimer, providing insights into ligand recognition, allosteric regulation, and G protein coupling mechanisms of DRD1.
Review
Pharmacology & Pharmacy
Karthik Ramesh, Daniel M. Rosenbaum
Summary: The cannabinoid CB1 receptor, as the most abundant G protein coupled receptor in the central nervous system, mediates the response to endocannabinoids and Cannabis compounds. Various ligands targeting CB1 receptors have been developed for the treatment of neurological disorders. High-resolution structures of CB1 receptor in different functional states have enhanced our understanding of CB1 ligand interactions, selectivity, receptor activation, and allosteric modulation, paving the way for the development of novel ligands for therapeutic applications.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
News Item
Biochemistry & Molecular Biology
Lin Cheng, Zhenhua Shao
Summary: The description of cryo-EM structures of CCKRs in active or inactive states provides insights into the molecular mechanisms of ligand recognition and G-protein-coupling, which can be utilized in developing therapeutic strategies targeting CCKRs signaling.
NATURE CHEMICAL BIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Varsha Ashok Walvekar, Karthik Ramesh, Chacko Jobichen, Muthu Kannan, J. Sivaraman, R. Manjunatha Kini, Yu Keung Mok
Summary: The specificity of Kazal-type protease inhibitors is determined by the sequence of the reactive-site loop. The crystal structure of Aedes aegypti trypsin inhibitor with mu-plasmin reveals differences in reactivities compared to other Kazal-type inhibitors. The scaffold instability of AaTI affects its ability to inhibit plasmin.
Article
Multidisciplinary Sciences
Xiao Teng, Sijia Chen, Yingying Nie, Peng Xiao, Xiao Yu, Zhenhua Shao, Sanduo Zheng
Summary: This study presents three cryo-electron microscopy structures of the D1 dopamine receptor (D1R)-Gs complex bound to three distinct D1R-selective drugs. The findings reveal the importance of drug binding modes for biased signaling.
NATURE COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Lin Cheng, Suyue Sun, Heli Wang, Chang Zhao, Xiaowen Tian, Ying Liu, Ping Fu, Zhenhua Shao, Renjie Chai, Wei Yan
Summary: In this study, the cryo-electron microscopy structure of Gi-coupled HCAR2 in complex with a selective agonist, MK-6892, was determined. It was found that MK-6892 occupies both the orthosteric binding pocket and an extended binding pocket within HCAR2. Pharmacological assays showed that the orthosteric binding pocket is crucial for ligand selectivity among the HCARs subfamily. Additionally, the probe-dependent behavior of the allosteric modulator compound 9n on HCAR2 was investigated.
SIGNAL TRANSDUCTION AND TARGETED THERAPY
(2023)
Article
Multidisciplinary Sciences
Karthik Ramesh, Varsha A. Walvekar, Benjamin Wong, Ahmed Mahmoud Mohammed Sayed, Dorothee Misse, R. Manjunatha Kini, Yu Keung Mok, Julien Pompon