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
Medicine, Research & Experimental
Yuanzi Zhao, Anand A. Joshi, Jane Aldrich, Thomas F. Murray
Summary: The study explored the utility of the real-time FLIPR Membrane Potential (FMP) assay in assessing kappa opioid receptor (KOR)-induced hyperpolarization. Results showed that the FMP assay is sensitive and can effectively evaluate the potential actions and efficacy of KOR ligands. Additionally, the study demonstrated that the FMP assay is useful for detecting the potency and efficacy of KOR-selective peptides.
BIOMEDICINE & PHARMACOTHERAPY
(2021)
Article
Cell Biology
Samantha M. McNeill, Jo-Anne Baltos, Paul J. White, Lauren T. May
Summary: Research has shown that utilizing biased agonism of adenosine receptor ligands can help avoid adverse effects and play a positive role in therapy.
CELLULAR SIGNALLING
(2021)
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)
Article
Multidisciplinary Sciences
Michelle D. Nemetchek, Ian M. Chrisman, Mariah L. Rayl, Andrew H. Voss, Travis S. Hughes
Summary: Efforts to decrease the adverse effects of nuclear receptor drugs have led to experimental agonists that produce better outcomes in mice. These agonists have been shown to cause different transcriptomic effects and a structural explanation for this remains unknown. The study reveals that partial agonists of the nuclear receptor peroxisome proliferator-associated receptor (PPAR) favor a different group of coactivator peptides compared to clinically used drugs, and differences in coactivator-PPAR bonding contribute to biased agonism. This provides a general structural mechanism for biased agonism in many nuclear receptors.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Cell Biology
Michael Ippolito, Jeffrey L. Benovic
Summary: β-adrenergic receptors consist of three subtypes and play important roles in regulating physiological processes. Developing biased agonists could potentially enhance treatment efficacy for diseases.
CELLULAR SIGNALLING
(2021)
Review
Pharmacology & Pharmacy
Claire Leconte, Raymond Mongeau, Florence Noble
Summary: Substance use disorders and traumatic stress-related pathologies often coexist. The KOR and DYN play a crucial role in this comorbidity, regulating the effects of stress and drug use. The DYN/KOR system is involved in anxiety, depressive symptoms, conditioned fear response, and negative reinforcement after drug use. KOR activation leads to drug-seeking behavior and cross-regulates with corticotropin-releasing factor. The sexual dimorphism of the DYN/KOR system may contribute to gender differences in patients with SUD or/and traumatic stress-related pathologies. Antagonists targeting KOR could be a promising pharmacological strategy for treating this comorbidity.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Cell Biology
H. Ongun Onaran, Tommaso Costa
Summary: This review discusses the theoretical and experimental foundations for assessing agonism in GPCRs, emphasizing the importance of separating efficacy from affinity in understanding agonism and identifying ligands with true bias of efficacy for unraveling the conformational space that determines the complex functional chemistry of GPCRs.
CELLULAR SIGNALLING
(2021)
Article
Neurosciences
Melanie M. Pina, Dipanwita Pati, Sofia Neira, Lisa R. Taxier, Christina M. Stanhope, Alexandra A. Mahoney, Shannon D'Ambrosio, Thomas L. Kash, Montserrat Navarro
Summary: Alcohol use disorder involves multiple signaling systems and brain regions. Previous studies have shown the involvement of the insular cortex and the DYN/KOR systems in excessive alcohol use. In this study, the role of insula DYN/KOR circuit components in alcohol intake was explored. The findings revealed distinct and sex-specific roles for insula DYN and KOR in alcohol drinking and related behavior.
JOURNAL OF NEUROSCIENCE
(2023)
Article
Pharmacology & Pharmacy
Caroline Baynard, Thomas E. Prisinzano, Eduardo R. Butelman
Summary: This study demonstrates that a novel KOR-antagonist can rapidly produce anti-immobility effects in a model of acute stress exposure.
FRONTIERS IN PHARMACOLOGY
(2021)
Review
Pharmacology & Pharmacy
Ben Jones
Summary: GLP-1 receptor agonists are effective treatments for type 2 diabetes by stimulating insulin release and promoting weight loss, but their main side effect is nausea. Recent studies suggest that biased GLP-1 agonists may achieve enhanced anti-hyperglycaemic efficacy by avoiding receptor desensitization and downregulation, particularly through reduced beta-arrestin recruitment, although more human data is needed for confirmation.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Article
Neurosciences
J. D. Lorente, J. Cuitavi, L. Rullo, S. Candeletti, P. Romualdi, L. Hipolito
Summary: This study analyzed the effects of pain on negative affect in different sexes and time courses, as well as the involvement of the dynorphinergic and corticotropin releasing factor systems in these pain-related behaviors. The results showed sex and time-dependent anxiety- and anhedonia-like behaviors induced by pain in female rats. The recruitment of KOR/DYN in the NAc was identified as a key neurological substrate mediating pain-induced behavioral alterations.
Review
Biochemistry & Molecular Biology
Andrea Bedini, Elisabetta Cuna, Monica Baiula, Santi Spampinato
Summary: Chronic pain is a significant burden, and there is a need to develop more effective and safer analgesics. G protein-biased opioid agonists have been extensively studied as improved analgesic candidates, but the complex pharmacology of opioid receptors remains a challenge in translating them into improved therapeutics.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Zhenmei Xu, Tatsuya Ikuta, Kouki Kawakami, Ryoji Kise, Yu Qian, Ruixue Xia, Ming-Xia Sun, Anqi Zhang, Changyou Guo, Xue-Hui Cai, Zhiwei Huang, Asuka Inoue, Yuanzheng He
Summary: This study reveals that p-arrestin-biased ligands direct a distinct activation path in S1PR1 through extensive interplay between the PIF and the NPxxY motifs, with key features including the intermediate flipping of W269(6.48) and the retained interaction between F265(6.44) and N307(7.49). The structural insights provided in this study offer a rational basis for designing novel signaling-biased S1PR modulators.
NATURE CHEMICAL BIOLOGY
(2022)
Article
Neurosciences
Tanya L. Wallace, William J. Martin, Amy F. T. Arnsten
Summary: This study demonstrates the protective role of KOR on working memory function and its crucial regulatory function under stress conditions. These findings provide important insights for the development of therapeutic strategies for stress-related neurobehavioral disorders.
NEUROBIOLOGY OF STRESS
(2022)
Article
Neurosciences
Nagendran Muthusamy, Xuying Zhang, Caroline A. Johnson, Prem N. Yadav, H. Troy Ghashghaei
NATURE NEUROSCIENCE
(2017)
Article
Chemistry, Medicinal
Lokesh Ravilla, N. Venkata Subba Naidu, Shalini Dogra, Deepmala Umrao, Prem N. Yadav, Ansuman Biswas, Daliah Michael, Kanagaraj Sekar, Kuppuswamy Nagarajan
JOURNAL OF MEDICINAL CHEMISTRY
(2017)
Article
Cell Biology
Punita Kumari, Ashish Srivastava, Eshan Ghosh, Ravi Ranjan, Shalini Dogra, Prem N. Yadav, Arun K. Shukla
MOLECULAR BIOLOGY OF THE CELL
(2017)
Article
Nanoscience & Nanotechnology
Eshan Ghosh, Ashish Srivastava, Mithu Baidya, Punita Kumari, Hemlata Dwivedi, Kumari Nidhi, Ravi Ranjan, Shalini Dogra, Akiko Koide, Prem N. Yadav, Sachdev S. Sidhu, Shohei Koide, Arun K. Shukla
NATURE NANOTECHNOLOGY
(2017)
Article
Chemistry, Medicinal
Rajesh Varkhedkar, Shalini Dogra, Divya Tiwari, Yusuf Hussain, Prem Narayan Yadav, Ganesh Pandey
Article
Neurosciences
Chandan Sona, Ajeet Kumar, Shalini Dogra, Boda Arun Kumar, Deepmala Umrao, Prem N. Yadav
NEUROBIOLOGY OF DISEASE
(2018)
Article
Chemistry, Medicinal
Kasireddy Sudarshan, Arun Kumar Boda, Shalini Dogra, Ishani Bose, Prem Narayan Yadav, Indrapal Singh Aidhen
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2019)
Article
Endocrinology & Metabolism
Ajeet Kumar, Shalini Dogra, Chandan Sona, Deepmala Umrao, Mamunur Rashid, Sandeep K. Singh, Muhammad Wahajuddin, Prem N. Yadav
PSYCHONEUROENDOCRINOLOGY
(2019)
Article
Chemistry, Medicinal
Ajeet Kumar, Venkata Reddy Pasam, Ravi Kumar Thakur, Maninder Singh, Kartikey Singh, Mahendra Shukla, Anubhav Yadav, Shalini Dogra, Chandan Sona, Deepmala Umrao, Swati Jaiswal, Hafsa Ahmad, Mamunur Rashid, Sandeep K. Singh, Muhammad Wahajuddin, Anil Kumar Dwivedi, Mohammad Imran Siddiq, Jawahar Lal, Rama Pati Tripathi, Prem N. Yadav
JOURNAL OF MEDICINAL CHEMISTRY
(2019)
Article
Neurosciences
Shalini Dogra, Branden J. Stansley, Zixiu Xiang, Weilun Qian, Rocco G. Gogliotti, Ferdinando Nicoletti, Craig W. Lindsley, Colleen M. Niswender, Max E. Joffe, P. Jeffrey Conn
Summary: Activation of mGlu3 receptors in hippocampal pyramidal cells enhances cognition in both control and impaired mice by inducing a novel form of metaplasticity to regulate circuit function, and reveals a mechanism by which mGlu3 and mGlu5 interact to enhance cognitive function.
BIOLOGICAL PSYCHIATRY
(2021)
Review
Neurosciences
Shalini Dogra, P. Jeffrey Conn
Summary: Compounds targeting mGlu receptors show promise as potential novel antidepressant strategies, with mGlu5 negative allosteric modulators and mGlu2/3 receptor antagonists demonstrating antidepressant effects in preclinical models. Despite inconclusive clinical trials, these compounds offer an exciting alternative for the development of safer and more efficacious antidepressants.
Article
Neurosciences
Max E. Joffe, Chiaki Santiago, Sheryl Anne D. Vermudez, Nicole M. Fisher, Shalini Dogra, Colleen M. Niswender, P. Jeffrey Conn
Summary: Prefrontal cortex dysregulation is a hallmark feature of several affective disorders, and mGlu(2/3) receptors may serve as potential targets for their treatment. Studies suggest that mGlu(3) receptors play a critical role in PFC pyramidal cells, and their knockdown could lead to anxiolytic effects and decreased passive coping behaviors.
NEUROPSYCHOPHARMACOLOGY
(2021)
Article
Multidisciplinary Sciences
Pritha Ghosh, Nishant Raj, Hitesh Verma, Monika Patel, Sohini Chakraborti, Bhavesh Khatri, Chandrashekar M. Doreswamy, S. R. Anandakumar, Srinivas Seekallu, M. B. Dinesh, Gajanan Jadhav, Prem Narayan Yadav, Jayanta Chatterjee
Summary: Solvent shielding of the amide hydrogen bond donor has been used to increase the membrane permeability of macrocyclic peptides, and this can also be achieved by masking the amide hydrogen bond acceptor. Thioamide substitution reduces the desolvation penalty and enhances the membrane permeability of the macrocycle. Thioamidation also improves the bioavailability and duration of action of the macrocyclic peptide.
NATURE COMMUNICATIONS
(2023)
Article
Chemistry, Multidisciplinary
Rewati Raman Ujjwal, Chandan Sona, Suman Debnath, Prem Narayan Yadav, Umaprasana Ojha