Article
Chemistry, Medicinal
Jiaying Xiong, Tao Zhuang, Yurong Ma, Junyi Xu, Jiaqi Ye, Ru Ma, Shuang Zhang, Xin Liu, Bi-Feng Liu, Chao Hao, Guisen Zhang, Yin Chen
Summary: This study describes the optimization, synthesis, and pharmacological activities of a new series of bifunctional piperidinamide derivatives as sigma-1 receptor antagonists and mu opioid receptor agonists. Compound 114 showed promising affinity and selectivity, with powerful dose-dependent analgesic effects and reduced opioid-like side effects compared to fentanyl. The pharmacokinetic properties of compound 114 were acceptable, suggesting its potential in treating neuropathic pain.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Mingxu Ma, Yifei Yang, Guangying Du, Yusen Dai, Xiaoyin Zhu, Wenyan Wang, Hengwei Xu, Jianzhao Zhang, Lixia Zheng, Fangxia Zou, Huijie Yang, Bin Liu, Wanhui Liu, Liang Ye, Rui Zhang, Jingwei Tian
Summary: Based on the docking study of Pimavanserin, a series of novel Pimavanserin derivatives were designed and synthesized. Compound 7-16 exhibited significantly higher 5-HT2A receptor antagonist and inverse agonist activities than Pimavanserin, along with improved pharmacokinetics and safety profile.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Ying Yun, Chenlu Zhang, Shimeng Guo, Xiaoying Liang, Yuan Lan, Min Wang, Ning Zhuo, Jianpeng Yin, Huanan Liu, Min Gu, Jing Li, Xin Xie, Fajun Nan
Summary: A new series of betulinic acid derivatives were identified as potent TGR5 agonists which showed species difference in activity, and a key amino acid H88 (Y89) was found to contribute to the species difference. Introducing the mTGR5 (H88Y) mutation in mice resulted in significant glucose-lowering effects and stimulated GLP-1 and insulin secretion, highlighting the potential for further investigation of TGR5 agonists.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Jae-Hoon Jung, In Hee Jang, Moon Young Yang, Sunhong Kim, Soo-Kyung Kim, William A. Goddard, Yong-Chul Kim
Summary: Chronic exposure to stress or unwanted stimuli can activate the KOR/DYN systems, leading to depressive states and psychiatric disorders. We discovered novel pyrazoloisoquinoline-based KOR beta-arrestin inverse agonists through synthesis, structure-activity relationships, optimization, and biological evaluations. The optimized compound 7q showed potent and selective beta-arrestin inverse agonism at KOR, with no activity at MOR and lower activities at DOR. Molecular dynamics simulations were used to predict the binding mode and propose a mechanism for the inverse agonism, revealing different interactions between the receptor and beta-arrestin in different OR subtypes.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Lin Lin, Guangyao Lin, Qingtong Zhou, Ross A. D. Bathgate, Grace Qun Gong, Dehua Yang, Qing Liu, Ming-Wei Wang
Summary: Relaxin family peptide receptors RXFPs are potential therapeutic targets for neurological, cardiovascular, and metabolic diseases, with RXFP3 and RXFP4 identified as promising targets for treatment. A new selective RXFP4 agonist was discovered through high-throughput screening, with structural modifications leading to a compound with improved selectivity and efficacy for RXFP4 compared to the original scaffold.
BIOORGANIC CHEMISTRY
(2021)
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
Chemistry, Medicinal
Veena D. Yadav, Lalan Kumar, Poonam Kumari, Sakesh Kumar, Maninder Singh, Mohammad I. Siddiqi, Prem N. Yadav, Sanjay Batra
Summary: The synthesis of new fused beta-carboline derivatives led to the discovery of two compounds with significant agonistic activity on KOR, which were found to be extremely G-protein-biased agonists. These compounds demonstrated analgesic effects in mice, without inducing sedation, and their interaction with the human KOR was studied for rationalization of the results.
Article
Chemistry, Medicinal
Salvatore Pacifico, Valentina Albanese, Davide Illuminati, Erika Marzola, Martina Fabbri, Federica Ferrari, Victor A. D. Holanda, Chiara Sturaro, Davide Malfacini, Chiara Ruzza, Claudio Trapella, Delia Preti, Ettore Lo Cascio, Alessandro Arcovito, Stefano Della Longa, Martina Marangoni, Davide Fattori, Romina Nassini, Girolamo Calo, Remo Guerrini
Summary: In this study, 31 peptides were synthesized and tested for their activity at human recombinant NOP/opioid receptors. The peptide [Dmt(1,5)]N/OFQ(1-13)-NH2 was identified as the most potent dual NOP/mu receptor agonist, with antitussive effects demonstrated in vivo. The molecular mechanisms of peptide binding to the mu receptor were elucidated through experimental and in silico studies.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biotechnology & Applied Microbiology
Maria de los Milagros Sales, Ricardo Kratje, Marcos Oggero, Natalia Ceaglio
Summary: Novel peptides tags GMOP and mGMOP were designed in this study, which were fused to human interferon to create new molecules with higher molecular masses and more negatively charged isoforms. These chimeras showed improved pharmacokinetic profiles in rats, with longer half-life and lower clearance rates, as well as enhanced in vitro thermal and plasma stability. Additionally, they were recognized by a monoclonal antibody in western blots and ELISAs, showing their potential as bifunctional tags for creating long-acting biotherapeutics.
JOURNAL OF BIOTECHNOLOGY
(2021)
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
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
Allergy
Mohna Bandyopadhyay, Adrian E. Morelli, Stephen C. Balmert, Nicole L. Ward, Geza Erdos, Tina L. Sumpter, Emrullah Korkmaz, Daniel H. Kaplan, Martin H. Oberbarnscheidt, Olga Tkacheva, William J. Shufesky, Louis D. Falo, Adriana T. Larregina
Summary: The study demonstrated the necessity of NK1R signaling in the development of contact dermatitis (CD) through substance P and hemokinin 1. Targeting NK1R in keratinocytes and dendritic cells prevented CD, while skin codelivery of hapten or Ag MNA inhibited neuropeptide-mediated skin inflammation and promoted regulatory T cells, preventing CD onset and relapses.
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Hyejin Park, Un-Ho Jin, Gregory Martin, Robert S. Chapkin, Laurie A. Davidson, Kyongbum Lee, Arul Jayaraman, Stephen Safe
Summary: Unsubstituted flavone can induce gene expression in Caco2 cells and acts as an AhR agonist. The addition of hydroxyl groups can determine the activity of flavones, but the affinity of mono- and dihydroxyflavones to AhR is similar and cannot accurately predict their activity. Most AhR-inactive flavones also function as AhR antagonists.
CHEMICO-BIOLOGICAL INTERACTIONS
(2022)
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, Multidisciplinary
Ranit Lahmy, Harald Hubner, Maximilian F. Schmidt, Daniel Lachmann, Peter Gmeiner, Burkhard Konig
Summary: This study developed photoswitchable ligands that can activate or deactivate clinically relevant mu-opioid receptors using light, allowing for spatial and temporal control of biological activity in various biological investigations. These ligands, modeled after the known agonist fentanyl, can change geometry upon exposure to light and have different photophysical and biochemical properties, which could be valuable in further studying the functional significance of the mu-opioid receptor.
CHEMISTRY-A EUROPEAN JOURNAL
(2022)
