Article
Biochemistry & Molecular Biology
Pramisha Adhikari, Bing Xie, Ana Semeano, Alessandro Bonifazi, Francisco O. Battiti, Amy H. Newman, Hideaki Yano, Lei Shi
Summary: The study focuses on developing D3R selective agonists over D2R and identifies compound AB04-88 with significant D3R selectivity and G protein bias. The chirality of the primary pharmacophore is key in conferring improved D3R potency, selectivity, and G protein signaling bias.
Article
Chemistry, Medicinal
Gui-Long Tian, Chia-Ju Hsieh, Michelle Taylor, Aladdin A. Riad, Robert R. Luedtke, Robert H. Mach
Summary: The difference in the secondary binding site between D2R and D3R has been utilized to design compounds with selectivity for D3R. This study prepared a series of bitopic ligands based on Fallypride to improve the selectivity for D3R using various secondary binding fragments. The results showed that compounds with a small alkyl group containing a heteroatom exhibited improved D3R selectivity.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Ho Young Kim, Ji Youn Lee, Chia-Ju Hsieh, Michelle Taylor, Robert R. Luedtke, Robert H. Mach
Summary: Previous studies have shown that endogenous dopamine competitively inhibits the binding of D-3 receptor antagonists. An SAR study on metoclopramide was conducted to develop an alternative scaffold for binding to the D-3 receptor. The study found that benzamide substituents and secondary binding fragments with aryl carboxamides resulted in excellent D-3 receptor affinities with subtype selectivity to the D-2 receptor.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Medicinal
Mingcheng Qian, Kuo Zhou, Yi Wu, Zhijie Luo, Zhekai Xiao, Jingjing Sun, Siyu Zeng, Yi Yao, Shuai Zhao, Xin Chen
Summary: The study identified a bitopic ligand 11 b as a potent D2R agonist with higher efficacy and subtype selectivity compared to the lead compound, suggesting that the optimal length of spacer affects D2R functionality. Molecular modeling showed that 11 b interacts with amino acid Asp114, contributing significantly to D2R functional activity. This compound could serve as a tool for further research.
Review
Psychiatry
Vanja Mandic-Maravic, Roberto Grujicic, Luka Milutinovic, Ana Munjiza-Jovanovic, Milica Pejovic-Milovancevic
Summary: Autism spectrum disorders (ASD) are characterized by impairment in social communication and repetitive behaviors. The causes of ASD are complex, involving both genetic and environmental factors. Current treatments only target the non-specific symptoms, and no specific treatment for the core symptoms of ASD has been developed.
FRONTIERS IN PSYCHIATRY
(2022)
Editorial Material
Clinical Neurology
Gavin P. Reynolds
Summary: Guidelines for schizophrenia treatment emphasize the importance of dosage and mechanism of action, particularly highlighting the benefits of partial agonist drugs in reducing side effects while maintaining efficacy.
JOURNAL OF PSYCHOPHARMACOLOGY
(2021)
Article
Chemistry, Medicinal
Jin Cai, Mingqi Huang, Yuhong Wang, Xixi Chen, Min Ji
Summary: Three series of novel bitopic benzopyranomorpholine analogues were designed, synthesized, and evaluated for their selective ligand activity for the dopamine D3 receptor. Most compounds showed strong binding affinities and selectivity for the D3 receptor. One compound, 20h, demonstrated nanomolar affinity for the D3 receptor and exhibited anti-drug addiction efficacy in animal models.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Chemistry, Medicinal
Francisco O. Battiti, Saheem A. Zaidi, Vsevolod Katritch, Amy Hauck Newman, Alessandro Bonifazi
Summary: This study investigates the role of regio- and stereochemistry in cyclic aliphatic linkers tethering pharmacophores targeting dopamine D-2 and D-3 receptors, introducing potent and selective agonists while modulating subtype selectivity in a stereospecific manner. The findings demonstrate a novel approach to modulate dopaminergic ligand pharmacology and introduce a new class of optically active cyclic linkers that can be utilized in expanding bitopic drug design towards other GPCRs. Extensive molecular docking studies support the pharmacological observations presented in the study.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Pharmacology & Pharmacy
Veronica Lunerti, Hongwu Li, Federica Benvenuti, Qianwei Shen, Ana Domi, Laura Soverchia, Rita Maria Concetta Di Martino, Giovanni Bottegoni, Carolina L. Haass-Koffler, Nazzareno Cannella
Summary: Tobacco use disorder is a worldwide health problem with limited efficacy in available medications. A study found that ARN15381, a multitarget compound with FAAH inhibition and DRD3 partial agonist activity, reduced nicotine self-administration in rats, suggesting the potential clinical importance of a multitarget approach in the treatment of tobacco use disorder.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2022)
Review
Psychiatry
Pavel Mohr, Jiri Masopust, Miloslav Kopecek
Summary: Dopamine receptor partial agonists (DRPAs) are a novel class of antipsychotics that have shown efficacy in the treatment of several psychiatric disorders. Although they have similar mechanisms of action, these drugs differ in their pharmacodynamics, pharmacokinetics, drug interactions, and safety profiles. Head-to-head comparisons between the three DRPA agents, aripiprazole, brexpiprazole, and cariprazine, are lacking. However, data from controlled trials, systematic reviews, and meta-analyses suggest that all three drugs have comparable acute antipsychotic effects and therapeutic benefits in specific psychiatric conditions.
FRONTIERS IN PSYCHIATRY
(2022)
Article
Biochemistry & Molecular Biology
Alessandro Bonifazi, Amy H. Newman, Thomas M. Keck, Silvia Gervasoni, Giulio Vistoli, Fabio Del Bello, Gianfabio Giorgioni, Pegi Pavletic, Wilma Quaglia, Alessandro Piergentili
Summary: The study identifies novel compounds targeting D3R or multiple targets, potentially useful for central nervous system disorders. Specific derivatives, such as 6,6-diphenyl-1,4-dioxane derivative 3 and 5,5-diphenyl-1,4-dioxane and 1,4-benzodioxane derivatives 6 and 9, display promising profiles for novel antipsychotic agents.
ACS CHEMICAL NEUROSCIENCE
(2021)
Article
Pharmacology & Pharmacy
Wei Xu, Frank Bearoff, Sandhya Kortagere
Summary: This study demonstrates that biased signaling agonists of D3R have differential effects on ERK1/2, which may be advantageous for the development of better drugs.
PHARMACOLOGICAL RESEARCH
(2022)
Review
Psychiatry
Xenia M. Hart, Christian N. Schmitz, Gerhard Gruender
Summary: This article reviews PET studies on partial agonist antipsychotics and highlights that optimal plasma levels derived from these studies can guide individualized treatment.
FRONTIERS IN PSYCHIATRY
(2022)
Review
Behavioral Sciences
Martin Osugo, Thomas Whitehurst, Ekaterina Shatalina, Leigh Townsend, Oisin O'Brien, Tsz Lun Allenis Mak, Robert McCutcheon, Oliver Howes
Summary: Dopamine dysfunction is closely related to the symptoms of schizophrenia. Medications that increase dopamine signaling, particularly dopamine D2/D3 partial agonists, have shown significant improvement in positive, negative, and total symptoms of schizophrenia compared to placebo. These findings support the clinical use of partial agonists for negative symptoms in schizophrenia.
NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS
(2022)
Article
Chemistry, Medicinal
Fengyu Huang, Zhiping Zeng, Weidong Zhang, Zhiqiang Yan, Jiayun Chen, Liangfa Yu, Qian Yang, Yihuan Li, Hongyu Yu, Junjie Chen, Caisheng Wu, Xiao-Kun Zhang, Ying Su, Hu Zhou
Summary: This study highlights the importance of meta-substitution in benzylidene moiety for PPARγ binding and activation, and the essential role of indene fluorine in regulating PPARγ. Compound 6b showed significant improvement in glucose tolerance in a diabetic model and exhibited no apparent toxicity to osteoblastic formation.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Pramisha Adhikari, Bing Xie, Ana Semeano, Alessandro Bonifazi, Francisco O. Battiti, Amy H. Newman, Hideaki Yano, Lei Shi
Summary: The study focuses on developing D3R selective agonists over D2R and identifies compound AB04-88 with significant D3R selectivity and G protein bias. The chirality of the primary pharmacophore is key in conferring improved D3R potency, selectivity, and G protein signaling bias.
Article
Biochemistry & Molecular Biology
Alessandro Bonifazi, Amy H. Newman, Thomas M. Keck, Silvia Gervasoni, Giulio Vistoli, Fabio Del Bello, Gianfabio Giorgioni, Pegi Pavletic, Wilma Quaglia, Alessandro Piergentili
Summary: The study identifies novel compounds targeting D3R or multiple targets, potentially useful for central nervous system disorders. Specific derivatives, such as 6,6-diphenyl-1,4-dioxane derivative 3 and 5,5-diphenyl-1,4-dioxane and 1,4-benzodioxane derivatives 6 and 9, display promising profiles for novel antipsychotic agents.
ACS CHEMICAL NEUROSCIENCE
(2021)
Article
Pharmacology & Pharmacy
Carolyn Tallon, Benjamin J. Bell, Anjali Sharma, Arindom Pal, Medhinee M. Malvankar, Ajit G. Thomas, Seung-Wan Yoo, Kristen R. Hollinger, Kaleem Coleman, Elizabeth L. Wilkinson, Sujatha Kannan, Norman J. Haughey, Rangaramanujam M. Kannan, Rana Rais, Barbara S. Slusher
Summary: Alzheimer's disease is characterized by the accumulation and spread of amyloid-beta and hyperphosphorylated tau. Recent research shows that conjugating the inhibitor DPTIP with a dendrimer delivery system improves its properties and effectively inhibits the spread of pTau in mice.
Article
Pharmacology & Pharmacy
Sadakatali S. Gori, Ajit G. Thomas, Arindom Pal, Robyn Wiseman, Dana Ferraris, Run-Duo Gao, Ying Wu, Jesse Alt, Takashi Tsukamoto, Barbara S. Slusher, Rana Rais
Summary: This study reports a distinct scaffold of D-DOPA as a GCPII inhibitor and evaluates its pharmacokinetics and inhibitory activity. The results show that the addition of the DAAO inhibitor sodium benzoate significantly enhances the exposure of D-DOPA in both plasma and brain, and D-DOPA is a noncompetitive, allosteric inhibitor of GCPII.
Article
Chemistry, Medicinal
Emma S. Gogarnoiu, Caleb D. Vogt, Julie Sanchez, Alessandro Bonifazi, Elizabeth Saab, Anver Basha Shaik, Omar Soler-Cedeno, Guo-Hua Bi, Benjamin Klein, Zheng-Xiong Xi, J. Robert Lane, Amy Hauck Newman
Summary: Highly selective dopamine D3 receptor (D3R) partial agonists/antagonists have not been successful for the treatment of psychostimulant use disorders (PSUD) due to low potency/efficacy or potential cardiotoxicity. This study suggests that moderately selective D3R/D2R partial agonists/antagonists may be effective in treating PSUD and comorbidities with other affective disorders. Cariprazine and its analogues showed promising results in reducing cocaine self-administration in rats.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Run-Duo Gao, Masahiro Maeda, Carolyn Tallon, Andrew P. Feinberg, Barbara S. Slusher, Takashi Tsukamoto
Summary: In this study, a series of 6-aminonicotinic acid esters were designed and synthesized as potential alternatives to 6-aminonicotinamide (6AN). One of these esters, compound Si, showed stronger antiproliferative activity and lower toxicity to primary neurons compared to 6AN.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Multidisciplinary Sciences
Rana Rais, Kathryn M. Lemberg, Lukas Tenora, Matthew L. Arwood, Arindom Pal, Jesse Alt, Ying Wu, Jenny Lam, Joanna Marie H. Aguilar, Liang Zhao, Diane E. Peters, Carolyn Tallon, Rajeev Pandey, Ajit G. Thomas, Ranjeet P. Dash, Tanguy Seiwert, Pavel Majer, Robert D. Leone, Jonathan D. Powell, Barbara S. Slusher
Summary: 6-Diazo-5-oxo-l-norleucine (DON) is a glutamine antagonist that suppresses cancer cell metabolism while enhancing the metabolic fitness of tumor CD8+ T cells. The development of DON was halted due to dose-limiting gastrointestinal toxicities. In order to overcome this, a DON peptide prodrug, DRP-104, was designed and showed improved tolerability and enhanced efficacy in tumor regression. The effect of DRP-104 is dependent on CD8+ T cells and results in strong immunologic memory.
Review
Chemistry, Medicinal
Alessandro Bonifazi, Fabio Del Bello, Gianfabio Giorgioni, Alessandro Piergentili, Elizabeth Saab, Luca Botticelli, Carlo Cifani, Emanuela Micioni Di Bonaventura, Maria Vittoria Micioni Di Bonaventura, Wilma Quaglia
Summary: Orexin-A and Orexin-B are highly conserved hypothalamic neuropeptides that mediate their effects through two distinct G protein-coupled receptors, OX1-R and OX2-R. They play important roles in various physiological functions such as sleep-wake cycle regulation, emotion, panic-like behaviors, anxiety/stress, food intake, and energy homeostasis. This review focuses on the medicinal chemistry aspects of small molecules acting as dual or subtype selective OX1-R/OX2-R agonists and antagonists, as well as radiolabeled OX-R ligands for molecular imaging.
MEDICINAL RESEARCH REVIEWS
(2023)
Article
Medicine, Research & Experimental
Kyungho Lee, Elizabeth A. Thompson, Sepideh Gharaie, Chirag H. Patel, Johanna T. Kurzhagen, Phillip M. Pierorazio, Lois J. Arend, Ajit G. Thomas, Sanjeev Noel, Barbara S. Slusher, Hamid Rabb
Summary: T cells in acute kidney injury (AKI) undergo metabolic reprogramming, and targeting the T cell glutamine pathway could be a promising therapeutic approach. Ischemic AKI in mice showed the presence of a distinct T cell subset with altered expression of certain metabolic proteins. Similarly, human nonischemic and ischemic kidney tissue exhibited similar findings. Inhibition of glutamine with JHU083 attenuated renal injury and reduced T cell activation and proliferation in AKI.
Article
Chemistry, Medicinal
Alessandro Bonifazi, Elizabeth Saab, Julie Sanchez, Antonina L. Nazarova, Saheem A. Zaidi, Khorshada Jahan, Vsevolod Katritch, Meritxell Canals, J. Robert Lane, Amy Hauck Newman
Summary: A new generation of dual-target μ opioid receptor (MOR) agonist/D3R antagonist/partial agonists was designed and synthesized. Through in vitro and in silico screening, new structural scaffolds were identified that achieved high affinity for MOR and D3R, improving receptor subtype selectivity and predicted blood-brain barrier permeability. Lead compounds have the potential for analgesic effects with reduced opioid-misuse liability via D3R antagonism.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Pharmacology & Pharmacy
Luca Botticelli, Emanuela Micioni Di Bonaventura, Fabio Del Bello, Gianfabio Giorgioni, Alessandro Piergentili, Wilma Quaglia, Alessandro Bonifazi, Carlo Cifani, Maria Vittoria Micioni Di Bonaventura
Summary: Neuromedin U (NMU) is a bioactive peptide involved in multiple physiological processes, acting through two G protein coupled receptors (GPCR). NMU plays a role in regulating food intake and has anti-obesity properties. It also influences binge eating behavior, suggesting its potential as a therapeutic target for obesity and eating disorders.
PHARMACOLOGICAL RESEARCH
(2023)
Article
Multidisciplinary Sciences
Abdul A. Waheed, Yanan Zhu, Eva Agostino, Lwar Naing, Yuta Hikichi, Ferri Soheilian, Seung- Wan Yoo, Yun Song, Peijun Zhang, Barbara S. Slusher, Norman J. Haughey, Eric O. Freed
Summary: This study demonstrates the essential role of nSMase2 in the morphogenesis and maturation of HIV-1 particles, as well as other primate lentiviruses. Inhibition or depletion of nSMase2 results in the production of immature and non-infectious viral particles.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Pharmacology & Pharmacy
Meixiang Huang, Carolyn Tallon, Xiaolei Zhu, Kaitlyn D. J. Huizar, Silvia Picciolini, Ajit G. Thomas, Lukas Tenora, Wathsala Liyanage, Francesca Roda, Alice Gualerzi, Rangaramanujam M. Kannan, Marzia Bedoni, Rana Rais, Barbara S. Slusher
Summary: In this study, the researchers used improved nanoparticles to deliver the inhibitor DPTIP and found its potential in inhibiting protein propagation in Alzheimer's disease. Further investigation revealed that the inhibitor only showed effect through its targeting of microglial cells. This highlights the importance of understanding cell-specific mechanisms when designing targeted therapies for Alzheimer's disease.
Article
Chemistry, Medicinal
Pegi Pavletic, Ana Semeano, Hideaki Yano, Alessandro Bonifazi, Gianfabio Giorgioni, Alessandro Piergentili, Wilma Quaglia, Maria Giovanna Sabbieti, Dimitrios Agas, Giorgio Santoni, Roberto Pallini, Lucia Ricci-Vitiani, Emanuela Sabato, Giulio Vistoli, Fabio Del Bello
Summary: In this paper, new ligands with high affinity and selectivity for D4R were discovered to better understand its role in GBM. The D4R antagonist 24 and biased ligand 29 showed the most potential and induced a decreased viability of GBM cells. Interestingly, these compounds had a greater effect in reducing cell viability compared to temozolomide, the first-choice chemotherapeutic drug in GBM.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Immunology
Benjamin J. Bell, Kristen R. Hollinger, Pragney Deme, Shinji Sakamoto, Yuto Hasegawa, David Volsky, Atsushi Kamiya, Norman Haughey, Xiaolei Zhu, Barbara S. Slusher
Summary: Combined antiretroviral therapy has improved the survival of people living with HIV, but they still face various cognitive, emotional, and physical issues. Research has found that overproduction of glutamate and upregulation of glutaminase activity in microglial cells could be linked to these problems. The brain-penetrant drug JHU083, which inhibits glutaminase activity, has shown potential in improving neurobehavioral phenotypes and restoring immune function in infected mice.
BRAIN, BEHAVIOR, & IMMUNITY - HEALTH
(2022)