Review
Chemistry, Medicinal
Shivani Jaiswal, Senthil Raja Ayyannan
Summary: Recently, FAAH and MAGL inhibitors have attracted attention for their potential anticancer effects. By regulating endogenous ligands, these inhibitors show therapeutic effects in chronic pain, metabolic disorders, psychoses, among others, and exhibit potential in various types of cancers.
Article
Biochemistry & Molecular Biology
Marta Baranowska-Kuczko, Hanna Kozlowska, Monika Kloza, Ewa Harasim-Symbor, Michal Biernacki, Irena Kasacka, Barbara Malinowska
Summary: Our study found that hypertension and chronic administration of the FAAH inhibitor URB597 have beneficial effects on the vascular endocannabinoid system in SHR, suggesting potential therapeutic benefits.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Neurosciences
Shirley Alteba, Anna Portugalov, Cecilia J. Hillard, Irit Akirav
Summary: Early-life stress and early cannabis use may increase the risk of psychopathologies, affecting behavior in male and female rats. Chronic FAAH inhibition during mid-adolescence did not prevent the long-term effects of ELS on behavior, while it ameliorated ELS-induced depression and anxiety-like behavior during late-adolescence. Sex-dependent alterations in CB1 receptors and GRs expression in the BLA-PFC-CA1 circuit may contribute to the depressive behavioral phenotype.
Article
Biology
Georgia Balsevich, Gavin N. Petrie, Daniel E. Heinz, Arashdeep Singh, Robert J. Aukema, Avery C. Hunker, Haley A. Vecchiarelli, Hiulan Yau, Martin Sticht, Roger J. Thompson, Francis S. Lee, Larry S. Zweifel, Prasanth K. Chelikani, Nils C. Gassen, Matthew N. Hill
Summary: A study found that the impact of FAAH C385A on metabolic outcomes is influenced by the environmental context. This genotype amplifies orexigenic responses and decreases anorexigenic responses, providing a potential explanation for the conflicting findings in previous human studies.
Article
Chemistry, Medicinal
Tugce Gur Maz, Sumeyye Turanli, H. Burak Caliskan, Burcu Caliskan, Erden Banoglu
Summary: A series of novel piperazine urea derivatives with thiadiazole moieties were designed, synthesized, and investigated for their inhibition potential against human fatty acid amide hydrolase (hFAAH). The urea derivatives possessing p-chlorophenylthiadiazole and benzylpiperazine fragments were identified as effective inhibitors of hFAAH, with compounds containing 4-chlorobenzyl and 4-fluorobenzyl tails showing the highest activity.
ARCHIV DER PHARMAZIE
(2022)
Review
Neurosciences
Shivanshu Bajaj, Shreshta Jain, Preeti Vyas, Sandhya Bawa, Divya Vohora
Summary: Alzheimer's disease is a neurodegenerative disease with potential therapeutic targets in the endocannabinoid system. Inhibitors of monoacylglycerol (MAGL) and fatty acid amide hydrolase (FAAH) possess multi-faceted properties for the treatment of Alzheimer's disease.
BRAIN RESEARCH BULLETIN
(2021)
Article
Biochemistry & Molecular Biology
Tiziana Genovese, Andrea Duranti, Ramona D'Amico, Roberta Fusco, Daniela Impellizzeri, Alessio Filippo Peritore, Rosalia Crupi, Enrico Gugliandolo, Salvatore Cuzzocrea, Rosanna Di Paola, Rosalba Siracusa, Marika Cordaro
Summary: Acute lung injury (ALI) is a lung disease characterized by severe inflammation without treatment. This study investigated the role of fatty acid amide hydrolase (FAAH) inhibition in an ALI mouse model and found that it could counteract the inflammatory response and histological changes caused by the disease.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Neurosciences
Yannick Fotio, Alex Mabou Tagne, Kwang-Mook Jung, Daniele Piomelli
Summary: In this study, the effects of two novel brain-permeable FAAH inhibitors, ARN14633 and ARN14280, were investigated in a rat model of predator stress-induced long-term anxiety. The results showed that these inhibitors effectively reduced anxiety-like behaviors and were correlated with the inhibition of FAAH activity and increase in FAAH substrate levels. This study supports the potential clinical application of FAAH inhibitors in the management of PTSD.
PSYCHOPHARMACOLOGY
(2023)
Article
Pharmacology & Pharmacy
Anugrah D. Santoso, Dirk De Ridder
Summary: Modulation of FAAH has immense potential as a new therapeutic candidate for several disorders, but further exploration is still needed to determine the best treatment strategy.
CANNABIS AND CANNABINOID RESEARCH
(2023)
Article
Urology & Nephrology
Jos G. A. Houbiers, J. W. Olivier van Till, Mathilde Kaper, Yalcin Yavuz, Reynaldo Martina, Dirk Cerneus, Joost Melis, Otto Stroosma, J. Curtis Nickel, Phil M. Hanno, Jorgen Nordling
Summary: This study evaluated the efficacy and safety of the fatty acid amide hydrolase (FAAH) inhibitor ASP3652 in patients with Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) and phenotyped patients based on Hunner's lesions (HL). ASP3652 was found to be safe and well tolerated in treatment, but did not demonstrate significant efficacy in IC/BPS. Differences observed between HL+ and HL- patients suggest that diagnosis and treatment of IC/BPS may need to be approached differently for these two phenotypes.
WORLD JOURNAL OF UROLOGY
(2021)
Article
Biochemistry & Molecular Biology
Emanuele Criscuolo, Maria Laura De Sciscio, Filomena Fezza, Mauro Maccarrone
Summary: Research suggests that the therapeutic efficacy of compounds targeted towards FAAH should be tested in vitro on both rat and human enzymes.
Review
Biochemistry & Molecular Biology
Dorsa Rafiei, Nathan J. Kolla
Summary: Studies have shown that increased FAAH expression is significantly correlated with depressive-like behaviors in animal models, and genetic knockout or pharmacological inhibition of FAAH can effectively reduce these behaviors in a dose-dependent manner. Differences in FAAH expression in depressive-like phenotypes are mainly localized in the animal prefrontal cortex, hippocampus, and striatum. Based on this, FAAH is considered a promising target for developing new pharmacotherapies for Major Depressive Disorder (MDD).
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Chemistry, Multidisciplinary
Stefan Rudolph, Helmut Dahlhaus, Walburga Hanekamp, Christian Albers, Maximilian Barth, Giulia Michels, Denise Friedrich, Matthias Lehr
Summary: A series of aryl N-[omega-(6-fluoroindol-1-yl)alkyl]-carbamates were synthesized and tested for inhibition of several important serine hydrolases. Most of the synthesized derivatives showed strong inhibition of FAAH, while some compounds also exhibited good inhibition of MAGL and BuChE. Some carbamates showed varying degrees of stability or inactivation towards esterases, with some forming covalent bonds with albumin.
Article
Biochemistry & Molecular Biology
Maddalena Grieco, Maria Giovanna De Caris, Elisa Maggi, Federica Armeli, Roberto Coccurello, Tiziana Bisogno, Maria D'Erme, Mauro Maccarrone, Patrizia Mancini, Rita Businaro
Summary: The study found that FAAH inhibition promotes microglial polarization towards an anti-inflammatory phenotype, reducing the expression of pro-inflammatory cytokines and increasing the release of anti-inflammatory cytokines, as well as enhancing cell phagocytosis.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Chemistry, Medicinal
Shivani Jaiswal, Senthil Raja Ayyannan
Summary: By utilizing a ligand-based design strategy, a series of isatin-3-carbohydrazones were synthesized and evaluated for their dual FAAH and MAGL inhibition properties. The study identified potent inhibitors, with compounds 13b and 13j being the most effective against MAGL and FAAH respectively, while compound 13c exhibited dual inhibitory activity and significant antioxidant properties in cell-based assays. These compounds showed promising pharmacokinetic profiles for treating neurological and mood disorders.
Article
Anesthesiology
Wisam Toma, Martial Caillaud, Nipa H. Patel, Tammy H. Tran, Giulia Donvito, Jane Roberts, Deniz Bagdas, Asti Jackson, Aron Lichtman, David A. Gewirtz, Alexandros Makriyannis, Michael S. Malamas, M. Imad Damaj
Summary: The study shows that paclitaxel reduces PEA levels in the spinal cord, while exogenous administration of PEA partially alleviates PIPN. Additionally, targeting NAAA enzyme with specific compound AM9053 can reverse and prevent PIPN. These findings suggest that selective NAAA inhibitors could be promising future therapeutics for the treatment and prevention of PIPN.
EUROPEAN JOURNAL OF PAIN
(2021)
Article
Nursing
Adriana V. Gaitan, JodiAnne T. Wood, Yingpeng Liu, Lipin Ji, Spyros P. Nikas, Alexandros Makriyannis, Carol J. Lammi-Keefe
Summary: This study found correlations between maternal dietary intake of long-chain polyunsaturated fatty acids and the concentrations of fatty acids and derived endocannabinoids in human milk. The inadequate intake of docosahexaenoic acid by participants was highlighted as a concern for infant development.
JOURNAL OF HUMAN LACTATION
(2021)
Article
Biochemistry & Molecular Biology
Basma G. Eid, Thikryat Neamatallah, Abeer Hanafy, Hany M. El-Bassossy, Lenah Binmahfouz, Hibah M. Aldawsari, Atif Hasan, Gamal Abd El-Aziz, Kiran Vemuri, Alexandros Makriyannis
Summary: The study investigated the effects of two neutral CB1 receptor antagonists, AM6545 and AM4113, on nephropathy associated with MetS in rats. Both compounds showed renal protective effects by inhibiting elevated proteinuria and albumin excretion rate, alleviating swelling and inflammatory cells infiltration in kidney structures, and preventing urine uric acid increase, collagen deposition, and elevated expression of TGF beta 1 in MetS animals. AM6545 and AM4113 interfered with TGF beta 1-mediated renal inflammation and fibrosis through peripheral action.
Article
Neurosciences
Despina Kokona, Dimitris Spyridakos, Manolis Tzatzarakis, Sofia Papadogkonaki, Eirini Filidou, Konstantinos Arvanitidis, George Kolios, Manjunath Lamani, Alexandros Makriyannis, Michael S. Malamas, Kyriaki Thermos
Summary: The endocannabinoid 2-AG has shown neuroprotective effects against excitotoxicity in the retina by activating CB1 and CB2 receptors as well as the PI3K/Akt signaling pathway. Inhibition of its metabolic enzymes, such as ABHD6 and MAGL, also provides partial neuroprotection against excitotoxicity in the retina.
Article
Chemistry, Medicinal
Thanh C. Ho, Marcus A. Tius, Spyros P. Nikas, Ngan K. Tran, Fei Tong, Han Zhou, Nikolai Zvonok, Alexandros Makriyannis
Summary: The novel oxa-adamantyl cannabinoids are identified as high affinity ligands for CB1 and CB2 cannabinoid receptors, showing potential as potent CB1 receptor agonists. Their synthesis is convenient, amenable to scale up, and suitable for large-scale preparation.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Chemistry, Medicinal
Shan Jiang, Christos Iliopoulos-Tsoutsouvas, Fei Tong, Christina A. Brust, Catherine M. Keenan, Jimit Girish Raghav, Tian Hua, Simiao Wu, Jo-Hao Ho, Yiran Wu, Travis W. Grim, Nikolai Zvonok, Ganesh A. Thakur, Zhi-Jie Liu, Keith A. Sharkey, Laura M. Bohn, Spyros P. Nikas, Alexandros Makriyannis
Summary: Novel cannabinergic probes have been developed to stabilize cannabinoid receptors through tight binding interactions, exhibiting high binding affinity and potent agonist activity. A key ligand, 27a, displays exceptional megagonist properties, acting centrally and peripherally, distinguishing it from previously reported megagonists.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Shrouq I. Farah, Samantha Hilston, Ngan Tran, Nikolai Zvonok, Alexandros Makriyannis
Summary: The interaction profiles of 2-AG, 1-AG, and 3-AG with endocannabinoid enzymes and CB1 receptor show differences in affinity and potency. The stereochemistry is crucial for the MGL enzyme, with 3-AG being the best substrate and 1-AG demonstrating the worst substrate profile. Both 1-AG and 3-AG are efficiently hydrolyzed by hABHD6 without preference.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2022)
Article
Neurosciences
Jenny L. Wilkerson, Lauren B. Alberti, Ganesh A. Thakur, Alexandros Makriyannis, Erin D. Milligan
Summary: CB2R agonists can impact the expression of TRPV1 in the spinal cord and DRG, critical for combating allodynia.
Article
Pharmacology & Pharmacy
Barbara Romano, Ester Pagano, Fabio A. Iannotti, Fabiana Piscitelli, Vincenzo Brancaleone, Giuseppe Lucariello, Maria Francesca Nani, Ferdinando Fiorino, Rosa Sparaco, Giovanna Vanacore, Federica Di Tella, Donatella Cicia, Ruggero Lionetti, Alexandros Makriyannis, Michael Malamas, Marcello De Luca, Giovanni Aprea, Maria D'Armiento, Raffaele Capasso, Bernardo Sbarro, Tommaso Venneri, Vincenzo Di Marzo, Francesca Borrelli, Angelo A. Izzo
Summary: The research shows the functional importance of N-acyl ethanolamine acid amidase (NAAA) in colorectal cancer (CRC) progression, with its inhibition counteracting tumor growth and affecting the composition of tumor secretome. NAAA is proposed as a valid drug target for the treatment of CRC growth and development.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Article
Chemistry, Medicinal
Ioannis P. Papanastasiou, Markos-Orestis Georgiadis, Christos Iliopoulos-Tsoutsouvas, Carol A. Paronis, Christina A. Brust, Ngan K. Tran, Lipin Ji, Xiaoyu Ma, JodiAnne T. Wood, Nikolai Zvonok, Fei Tong, Laura M. Bohn, Spyros P. Nikas, Alexandros Makriyannis
Summary: This study merged the features of nabilone and AM2389 and optimized the C3 side chain. Among the nabilone analogs, AM8936 exhibited balanced and potent agonist activity on the CB1 receptor, making it a potential candidate for further development.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Arman A. Sadybekov, Anastasiia Sadybekov, Yongfeng Liu, Christos Iliopoulos-Tsoutsouvas, Xi-Ping Huang, Julie Pickett, Blake Houser, Nilkanth Patel, Ngan K. Tran, Fei Tong, Nikolai Zvonok, Manish K. Jain, Olena Savych, Dmytro S. Radchenko, Spyros P. Nikas, Nicos A. Petasis, Yurii S. Moroz, Bryan L. Roth, Alexandros Makriyannis, Vsevolod Katritch
Summary: Structure-based virtual ligand screening using V-SYNTHES method is effective in rapidly identifying high-scoring compounds from a large chemical space, with experimental results demonstrating successful hit rates and potencies. This approach shows promise for lead discovery and is easily scalable for use with diverse docking algorithms.
Article
Anesthesiology
Xiaoyan Lin, Zhili Xu, Lawrence Carey, Julian Romero, Alexandros Makriyannis, Cecilia J. Hillard, Elizabeth Ruggiero, Marilyn Dockum, George Houk, Ken Mackie, Phillip J. Albrecht, Frank L. Rice, Andrea G. Hohmann
Summary: This study investigated the cell types expressing CB2 receptor and found that CB2 expressed in previously unrecognized populations of skin cells may serve as a potential target for suppressing chemotherapy-induced neuropathic pain.
Article
Multidisciplinary Sciences
Othman Benchama, Sergiy Tyukhtenko, Michael S. Malamas, Mark K. Williams, Alexandros Makriyannis, Hava Karsenty Avraham
Summary: This study found that the use of MAGL inhibitor AM9928 can effectively block the adhesion and migration of TNBC cells, reduce the secretion of pro-inflammatory factors by cells, and inhibit the activation of HBMECs and cytokine secretion caused by TNBC. Animal experiments showed that AM9928 can inhibit the growth of mammary tumors in the mammary fat pads and reduce the permeability changes of the blood brain barrier, thus reducing the metastasis of TNBC in the brain. These findings suggest that MAGL inhibitors have the potential to be a novel strategy for TNBC treatment.
SCIENTIFIC REPORTS
(2022)
Correction
Chemistry, Medicinal
Thanh C. Ho, Joseph J. Mullins, Marcus A. Tius, Spyros P. Nikas, Ngan K. Tran, Fei Tong, Nicolai Zvonok, Alexandros Makriyannis
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Cell Biology
Suthakar Ganapathy, Jian Liu, Tianqi Yu, Rui Xiong, Qiang Zhang, Alexandros Makriyannis, Changyan Chen
Summary: Hexavalent chromium (Cr(VI)) pollution is a serious environmental and health concern. This study reveals the role of protein kinase C (PKC) in Cr(VI)-induced carcinogenesis and drug resistance, and suggests that PKC can be a potential biomarker for early detection of health damages and a therapeutic target for developing new treatments for diseases caused by Cr(VI).
Article
Chemistry, Medicinal
Shibin Zhao, Julian Maceren, Mia Chung, Samantha Stone, Raphael Geiben, Melissa L. Boby, Bradley S. Sherborne, Derek S. Tan
Summary: Antibiotic resistance is a major threat to public health, with Gram-negative bacteria presenting unique challenges due to their low permeability and efflux pumps. Limited understanding of the chemical rules for overcoming these barriers hinders antibacterial drug discovery. Efforts to address this issue, such as screening compound libraries and using cheminformatic analysis, have led to the design of sulfamidoadenosines with diverse substituents, showing potential utility in accumulation in Escherichia coli.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Jichun Li, Qing Li, Shuai Xia, Jiahuang Tu, Longbo Zheng, Qian Wang, Shibo Jiang, Chao Wang
Summary: This study successfully developed a short peptide mimetic as a MERS-CoV fusion inhibitor by reproducing the key recognition features of the HR2 helix. The resulting 23-mer lipopeptide showed comparable inhibitory effect to the 36-mer HR2 peptide HR2P-M2. This has important implications for developing short peptide-based antiviral agents to treat MERS-CoV infection.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Krista Jaunsleine, Linda Supe, Jana Spura, Sten van Beek, Anna Sandstrom, Jessica Olsen, Carina Halleskog, Tore Bengtsson, Ilga Mutule, Benjamin Pelcman
Summary: Beta(2)-adrenergic receptor agonists can stimulate glucose uptake by skeletal muscle cells and are therefore potential treatments for type 2 diabetes. The chirality of compounds has a significant impact on the activity of these agonists. This study found that certain synthesized compounds showed higher glucose uptake activity. These findings provide important information for the design of novel beta(2)AR agonists for T2D treatment.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Xin Xu, Jia Chen, Guan Wang, Xiaojuan Zhang, Qiang Li, Xiaobo Zhou, Fengying Guo, Min Li
Summary: The study focuses on EZH2, a promising therapeutic target for various types of cancers. Researchers designed and synthesized a series of novel derivatives aiming to enhance the EZH2 inhibition activity. Among them, compound 28 displayed potent EZH2 inhibition activity and showed high anti-proliferative effects in lymphoma cell lines and xenograft mouse models. The study suggests that compound 28 has potential as a therapeutic candidate for EZH2-associated cancers.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Wei Zhang, Wei Liu, Ya-Dong Zhao, Li-Zi Xing, Ji Xu, Rui-Jun Li, Yun-Xiao Zhang
Summary: This study developed a series of aromatic amide derivatives based on Rhein and investigated their inhibitory activity against alpha-Syn aggregation. Two of these compounds showed promising potential in treating Parkinson's disease by stabilizing alpha-Syn's conformation and disassembling alpha-Syn oligomers and fibrils.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Mani Sharma, S. S. S. S. Sudha Ambadipudi, Neeraj Kumar Chouhan, V. Lakshma Nayak, Srihari Pabbaraja, Sai Balaji Andugulapati, Ramakrishna Sistla
Summary: Therapeutically active lipids in drug delivery systems can enhance the safety and efficacy of treatment. The liposome formulation created using synthesized biologically active lipids showed additive anti-cancer effects and reduced tumorigenic potential.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
