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.
Review
Biochemistry & Molecular Biology
Federica Santino, Luca Gentilucci
Summary: Researchers are striving to find selective KOR agonists that can activate beneficial signals without causing side effects, and partial agonists are also expected to produce analgesia while minimizing adverse effects. Recent trends in the design of KOR-selective, biased or partial, and peripherally acting agonists are discussed in this review.
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
Biochemistry & Molecular Biology
Analia Young Hwa Cho, Hery Chung, Javier Romero-Parra, Poulami Kumar, Marco Allara, Alessia Ligresti, Carlos Gallardo-Garrido, Hernan Pessoa-Mahana, Mario Faundez, Carlos David Pessoa-Mahana
Summary: The endocannabinoid system (ECS) is a broad-spectrum modulator of homeostasis in mammals, offering therapeutic opportunities for various pathologies. In this study, a new library of compounds targeting the CB2 receptor was synthesized by combining natural product motifs with a benzo[d]imidazole scaffold. SAR analysis revealed the importance of bulky aliphatic or aromatic natural product motifs in receptor recognition.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemical Research Methods
Marie H. Deventer, Katleen Van Uytfanghe, Inge M. J. Vinckier, Fabiano Reniero, Claude Guillou, Christophe P. Stove
Summary: In recent years, countries have implemented measures to control the increase of new synthetic cannabinoid receptor agonists (SCRAs) in the recreational drug market. China implemented a new legislation in July 2021, banning SCRAs with seven core scaffolds. This study reports on the potency and efficacy of five members of a new class of SCRAs, providing important information for public health officials, law enforcement agencies, and clinicians.
DRUG TESTING AND ANALYSIS
(2022)
Review
Biochemistry & Molecular Biology
Valeria Gasperi, Tatiana Guzzo, Alessandra Topai, Nicola Gambacorta, Fulvio Ciriaco, Orazio Nicolotti, Mauro Maccarrone
Summary: In the past decade, there has been a significant focus on developing selective modulators of the type-2 cannabinoid receptor (CB2) to target endocannabinoid signaling in humans. CB2 plays an active role in regulating various physiological and pathological processes, making it a promising target for therapeutic drugs. Recent studies have highlighted the protective effects of CB2 in central nervous system disorders, bone and synovial diseases, and cancer. Advances in the development of CB2 agonists have been correlated with different chemical classes and diverse therapeutic applications, and the elucidation of CB2 tertiary structure has provided new insights for the design of more selective agonists.
CURRENT MEDICINAL CHEMISTRY
(2023)
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
Yuan-yuan Wei, Yan Ma, Song-yu Yao, Ling-hui Kong, Xiao Liu, Jing-rui Chai, Jing Chen, Wei Li, Yu-jun Wang, Li-ming Shao, Jing-gen Liu
Summary: SLL-039 and SLL-1206 are potent and long-lasting analgesic agents with antipruritic effects, showing potential as novel analgesics with fewer side effects. They activate K opioid receptors and do not cause sedation or conditioned place aversion, suggesting their promise as effective pain relief options.
ACTA PHARMACOLOGICA SINICA
(2022)
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)
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)
Review
Oncology
Qier Zhou, Zhiwei Zhang, Songkai Long, Wanjun Li, Baiyun Wang, Na Liang
Summary: The kappa-opioid receptor (KOR) is associated with various types of cancer and understanding this association may facilitate the development of new antitumor therapies.
MOLECULAR MEDICINE REPORTS
(2022)
Article
Biology
Sebastian Fritzwanker, Falko Nagel, Andrea Kliewer, Viviane Stammer, Stefan Schulz
Summary: Phosphorylation of receptors is unstable during routine immunohistochemical procedures, requiring the use of phosphatase inhibitors for specific GPCR antibodies. We showed that phosphorylation of receptors is highly unstable during routine immunohistochemical procedures, and the use of phosphatase inhibitors is necessary for specific GPCR antibodies. Our findings were confirmed using phosphorylation state-specific MOP and CB1 antibodies.
COMMUNICATIONS BIOLOGY
(2023)
Review
Surgery
Adam Makaro, Lukasz Dziki, Jakub Fichna, Marcin Wlodarczyk
Summary: Calprotectin, a protein involved in innate immune responses and inflammatory processes, is found to be valuable in diagnosing inflammatory gastrointestinal diseases. Studies have shown that fecal and serum calprotectin can provide additional diagnostic information, with fecal calprotectin being considered a promising biomarker due to its high resistance to degradation in stool. Innovative methods like neural networks may play a valuable role in developing diagnostic panels for acute appendicitis, which is still in need of sensitive and specific markers according to current literature.
INDIAN JOURNAL OF SURGERY
(2022)
Article
Gastroenterology & Hepatology
Jesse J. DiCello, Simona E. Carbone, Ayame Saito, Vi Pham, Agata Szymaszkiewicz, Arisbel B. Gondin, Sadia Alvi, Kiliana Marique, Priyank Shenoy, Nicholas A. Veldhuis, Jakub Fichna, Meritxell Canals, Arthur Christopoulos, Celine Valant, Daniel P. Poole
Summary: This study investigates the modulation of delta opioid receptor in the enteric nervous system using allosteric modulators, demonstrating the potential of positive allosteric modulation as a pharmacological approach to enhance opioid receptor signaling and suppress colonic motility. The findings suggest that allosteric modulation of opioid receptor signaling could be a therapeutic strategy for conditions such as irritable bowel syndrome.
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Agata Gurba, Przemyslaw Taciak, Mariusz Sacharczuk, Izabela Mlynarczuk-Bialy, Magdalena Bujalska-Zadrozny, Jakub Fichna
Summary: Cancer is a major cause of illness and death worldwide. Colorectal cancer is the third most common cancer in men and the second most common in women. Standard antitumor therapies, such as cisplatin, have limitations due to their lack of specificity for tumor cells, drug resistance development, and severe side effects. Therefore, new methods and strategies for treating colorectal cancer are urgently needed. Current research focuses on novel platinum and other metal-based drugs, such as gold, silver, iridium, or ruthenium. Au(III) compounds are considered promising candidates for colorectal cancer treatment due to their structural similarity to Pt(II). However, their stability under physiological conditions needs improvement by combining with various ligands. This review summarizes the progress in developing stable Au(III) complexes with potential cytotoxic activity against cancer cells. Additionally, it highlights that the anticancer effects of Au derivatives are mediated by protein structures, such as thioredoxin reductase, rather than nucleic acids. The current state of in vivo studies is also discussed.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Agata Szymaszkiewicz, Marcin Talar, Jakub Wlodarczyk, Mikolaj Swierczynski, Adrian Bartoszek, Julia Krajewska, Anna Mokrowiecka, Ewa Malecka-Wojciesko, Jakub Fichna, Marta Zielinska
Summary: Nearly 20% of elderly patients suffer from constipation, but the age-related changes in the gastrointestinal (GI) tract remain insufficiently elucidated. This study evaluated the alterations within the endogenous opioid system (EOS) as a potential cause of constipation in the elderly. The results showed that the age-related impairment of GI peristalsis may result from reduced MOP and DOP response to opioid agonists or alterations in EOS expression.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Medicine, Research & Experimental
Tomasz Mackiewicz, Jakub Wlodarczyk, Marta Zielinska, Marcin Wlodarczyk, Adam Durczynski, Piotr Hogendorf, Lukasz Dziki, Jakub Fichna
Summary: This study measured the expression of GPR35 in colorectal cancer (CRC) and pancreatic adenocarcinoma (PDAC) patients using real-time polymerase chain reaction (RT-PCR). The results showed significantly higher GPR35 expression in tumor samples compared to paired healthy samples, and correlations with tumor characteristics were observed. These findings suggest the potential prognostic value of GPR35 testing in CRC and PDAC patients.
ADVANCES IN CLINICAL AND EXPERIMENTAL MEDICINE
(2023)
Review
Medicine, General & Internal
Jakub Wlodarczyk, Jacek Burzynski, Bartlomiej Czerwinski, Mateusz Prusisz, Katarzyna Socala, Ewa Poleszak, Jakub Fichna, Kasper Marynczak, Marcin Wlodarczyk, Lukasz Dziki
Summary: Crohn's disease is a subtype of chronic inflammatory bowel diseases characterized by skip lesions and transmural inflammation. It can affect the entire gastrointestinal tract and persistent pain is one of the main symptoms. This study aims to provide an abbreviated summary of the current knowledge on the origins and treatment of pelvic pain in Crohn's disease.
JOURNAL OF CLINICAL MEDICINE
(2023)
Article
Pharmacology & Pharmacy
Marek Pajak, Magdalena Wozniczka, Miroslawa Swiatek, Bartlomiej Czerwinski, Jakub Wlodarczyk, Jakub Fichna
Summary: The complexation properties of two synthetic nucleosides, beta-D-ribofuranoside-4-pyrimidinone (ribo) and beta-D-deoxyribofuranoside-4-pyrimidinone (deoxy), with Ag(I) ions in aqueous solution were investigated. The stability constants of the coordination entities formed were calculated and the percentage of each entity in solution was estimated. The results suggest that these coordination entities have potential antiviral, antibacterial, and antitumor properties, as well as potential applications in nanobiotechnology.
ACTA POLONIAE PHARMACEUTICA
(2023)
Review
Pharmacology & Pharmacy
Karolina Merecz, Mikolaj Hirsa, Olga Biniszewska, Jakub Fichna, Aleksandra Tarasiuk
Summary: Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder that affects approximately 10% of the global population. Recent studies have shown that antagonism of the serotonin 5-HT3 receptor is an effective treatment for IBS-D. The modulation of serotonin function plays a crucial role in maintaining intestinal homeostasis.
EXPERT OPINION ON PHARMACOTHERAPY
(2023)
Article
Biochemistry & Molecular Biology
Jakub Wlodarczyk, Julia Krajewska, Lukasz Szeleszczuk, Patrycja Szalwinska, Agata Gurba, Szymon Lipiec, Przemyslaw Taciak, Remigiusz Szczepaniak, Izabela Mlynarczuk-Bialy, Jakub Fichna
Summary: Inflammatory bowel diseases (IBD), such as Crohn's disease and ulcerative colitis, are global health problems with increasing frequency and unclear pathogenesis. Current treatment involves drugs like corticosteroids and derivative compounds, but more specific and effective therapies are desired. In this study, novel gold complexes were tested and found to have anti-inflammatory potential both in vitro and in vivo, particularly TGS 703, which was able to alleviate inflammation in a mouse model of colitis and showed a link to antioxidant systems. These findings suggest that gold(III) complexes may have therapeutic applications in the treatment of IBD.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Pharmacology & Pharmacy
Jacek Burzynski, Jakub Fichna, Aleksandra Tarasiuk
Summary: Acute pancreatitis (AP) and chronic pancreatitis (CP) are severe diseases that pose a great threat to human health in high-income countries. Oxidative stress plays a significant role in the development of AP and CP, and there is growing interest in the use of antioxidant therapy to manage these conditions. Vitamin A, a well-known antioxidant, has been understudied in relation to its impact on oxidative stress in AP and CP. This review aims to evaluate the molecular targets of vitamin A and its potential role in attenuating oxidative stress in AP and CP. The findings suggest that vitamin A may influence several molecular pathways involved in antioxidative defense and cytoprotection, indicating its potential to alter the disease course of AP and CP.
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
(2023)
Article
Toxicology
Szymon Lipiec, Agata Gurba, Izabela M. Agnieszczak, Andrzej Antoni Szczepankiewicz, Przemyslaw Szymanski, Przemyslaw Taciak, Remigiusz Szczepaniak, Lukasz Szeleszczuk, Hanna Nieznanska, Jakub Wlodarczyk, Jakub Fichna, Lukasz P. Bialy, Izabela Mlynarczuk-Bialy
Summary: Metal-based agents in cancer therapy, like cisplatin and its derivates, have established clinical applications but also can induce serious side effects. Thus, metallotherapeutic alternatives for platinum derivatives are developed and intensively studied. Platinum is replaced by several transition metals including gold. Especially gold (III) complexes can have the same square-planar structure and are isoelectric with platinum (II).
TOXICOLOGY IN VITRO
(2023)
Article
Immunology
Adam Makaro, Mikolaj Swierczynski, Kacper Pokora, Barbara Sarniak, Radzislaw Kordek, Jakub Fichna, Maciej Salaga
Summary: Inflammatory bowel diseases (IBD) is a chronic and relapsing inflammation in the gastrointestinal tract. The incidence and prevalence of IBD are high and increasing, and current therapeutic strategies are suboptimal. This study focused on gliflozins, a group of anti-diabetic drugs, and found that they have anti-inflammatory properties. In vitro experiments showed that two gliflozins, EMPA and DAPA, suppressed nitric oxide production in macrophages, and in vivo experiments demonstrated that EMPA alleviated colitis in mice. Our findings suggest that SGLT-2 inhibitors have anti-inflammatory effects independent of their hypoglycemic effects.
INFLAMMOPHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Marcin Sochal, Marta Ditmer, Agata Binienda, Agata Gabryelska, Piotr Bialasiewicz, Renata Talar-Wojnarowska, Jakub Fichna, Ewa Malecka-Wojciesko
Summary: Inflammatory bowel disease (IBD) patients often experience sleep and mood disorders which may be related to the disruption of the brain-gut axis. This study found that IBD patients had lower expression of BDNF mRNA but higher concentrations of proBDNF and BDNF protein compared to healthy controls. BDNF protein levels were positively correlated with sleep efficiency in the IBD group and depression severity was associated with BDNF mRNA and protein levels in the remission group.
Article
Medicine, General & Internal
Marcin Sochal, Alicja Witkowska, Agata Binienda, Agata Gabryelska, Piotr Bialasiewicz, Jakub Fichna, Renata Talar-Wojnarowska, Ewa Malecka-Wojciesko
Summary: The study investigates the impact of the serotonergic pathway on the pathogenesis and course of inflammatory bowel diseases (IBDs), and its relationship with sleep and mood disorders. The results show that patients with active IBD have higher levels of 5-HT and SERT protein expression, which are positively correlated with insomnia severity. After treatment, only 5-HT levels are decreased.
JOURNAL OF CLINICAL MEDICINE
(2023)
Review
Biology
Marcin Wlodarczyk, Adam Makaro, Mateusz Prusisz, Jakub Wlodarczyk, Marta Nowocien, Kasper Marynczak, Jakub Fichna, Lukasz Dziki
Summary: Crohn's disease (CD) is a chronic, relapsing inflammatory bowel disease characterized by transmural inflammation in the gastrointestinal tract. Chronic fatigue is a common and often underestimated symptom in CD patients, with a higher prevalence compared to the general population. Its underlying causes and mechanisms are complex and not fully understood. Routine screening and a comprehensive, multidisciplinary approach, including psychological support, may play a crucial role in managing CD patients with chronic fatigue. Further research is needed to predict, prevent, identify, and treat fatigue associated with CD. This review aims to summarize the current knowledge on the etiology, diagnosis, and treatment of chronic fatigue in CD patients.
