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)
Article
Chemistry, Inorganic & Nuclear
Crist N. Filer, Joseph R. Andrews, Scot Pounds, Giliyar Ullas
Summary: This study presents an efficient method for radiolabeling several dopamine D-2 receptor agonists with tritium at high specific activity.
APPLIED RADIATION AND ISOTOPES
(2021)
Article
Chemistry, Medicinal
Wenzhong Yan, Luyu Fan, Jing Yu, Ruiquan Liu, Huan Wang, Liang Tan, Sheng Wang, Jianjun Cheng
Summary: The novel compounds based on PCPMA scaffold were designed and synthesized, resulting in the identification of potent D2R partial agonists with good pharmacokinetic properties and unexpected selectivity against the 5-HT2A receptor. These PCPMA-derived D2R partial agonists showed suppressive effects in a mouse hyperlocomotion model, indicating their potential as novel antipsychotics.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
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.
Article
Biochemistry & Molecular Biology
Radomir Juza, Kristyna Stefkova, Wim Dehaen, Alena Randakova, Tomas Petrasek, Iveta Vojtechova, Tereza Kobrlova, Lenka Pulkrabkova, Lubica Muckova, Marko Mecava, Lukas Prchal, Eva Mezeiova, Kamil Musilek, Ondrej Soukup, Jan Korabecny
Summary: In this pilot study, a series of new 3,4-dihydroquinolin-2(1H)-one derivatives were synthesized and evaluated as potential dopamine receptor D-2 (D2R) modulators. Compound 5e showed the highest D2R affinity among the synthesized compounds, with low cytotoxicity and high blood-brain barrier penetration probability. However, molecular modelling simulation revealed a different binding mode of 5e compared to USC-D301, possibly explaining the reduced affinity of 5e towards D2R.
Review
Neurosciences
Tetsuro Kikuchi, Kenji Maeda, Mikio Suzuki, Tsuyoshi Hirose, Takashi Futamura, Robert D. McQuade
Summary: Otsuka Pharmaceutical has made significant achievements in the field of antipsychotic drug discovery by successfully developing dopamine D-2 receptor partial agonists for the treatment of schizophrenia and other conditions. Their efforts have led to the approval of medications like aripiprazole and brexpiprazole in multiple countries for various indications.
NEUROPSYCHOPHARMACOLOGY REPORTS
(2021)
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
Chemistry, Physical
Parisa Amani, Razieh Habibpour, Leila Karami
Summary: This study investigated the interaction between two derivatives of aripiprazole and the D2 receptor through chemoinformatics appraisal, molecular docking, and molecular dynamics simulations. The research found that both derivatives exhibited strong binding to the D2 receptor and induced noticeable rearrangements in intracellular regions.
JOURNAL OF MOLECULAR LIQUIDS
(2022)
Article
Biochemistry & Molecular Biology
Ana Jalles, Carmen Vieira, Joana Pereira-Sousa, Daniela Vilasboas-Campos, Ana Francisca Mota, Sara Vasconcelos, Bruna Ferreira-Lomba, Marta Daniela Costa, Jorge Diogo Da Silva, Patricia Maciel, Andreia Teixeira-Castro
Summary: Aripiprazole, an atypical antipsychotic drug, has been approved by the FDA for the treatment of psychotic, mood, and other psychiatric disorders. It has been found to effectively suppress the pathogenesis of Machado-Joseph disease and reduce the abundance and aggregation of mutant ATXN3 proteins. This study identifies dopamine D-2-like and serotonin 5-HT1A and 5-HT2A receptors as critical targets for aripiprazole-mediated improvements in motor function.
Article
Biochemistry & Molecular Biology
Dayana Rodriguez-Contreras, Alec F. Condon, David C. Buck, Naeem Asad, Timothy M. Dore, Dineke S. Verbeek, Marina A. J. Tijssen, Ujwal Shinde, John T. Williams, Kim A. Neve
Summary: A novel dopamine D2 receptor mutation was found to be constitutively active and signaling-biased, with enhanced basal activation and reduced arrestin recruitment compared to the wild type receptor. The impact of this variant in a specific brain region may vary depending on the expression levels of G proteins and GRK.
ACS CHEMICAL NEUROSCIENCE
(2021)
Review
Pharmacology & Pharmacy
Mattia Ferraiolo, Emmanuel Hermans
Summary: L-DOPA and dopamine agonists are key therapeutic options for managing the motor symptoms of Parkinson's disease. Despite similarities in their mechanism of action, pramipexole, ropinirole, and rotigotine have distinct clinical profiles possibly due to differences in their pharmacological properties. This review aims to explore the properties of these dopamine agonists from both clinical and molecular perspectives, providing a unified framework for interpretation.
PHARMACOLOGY & THERAPEUTICS
(2023)
Article
Pharmacology & Pharmacy
Adiba Anam, Sean Lynch, Nafiz Mosharraf, Chloe Soukas, Dmitriy Gekhman
Summary: Schizophrenia is a common psychiatric illness with significant economic and social burden. Second generation antipsychotics, including Aripiprazole, Risperidone, and Paliperidone, have changed treatment practices for psychiatrists. Aripiprazole has high affinity for the dopamine D2 receptor, which is responsible for the antipsychotic effect, but may not be as potent as other second generation antipsychotics. This case study explores how Aripiprazole may worsen psychiatric symptoms by blocking the antipsychotic effects of Paliperidone due to its strong binding affinity for the D2 receptor. Prescribers should be cautious when initiating long-acting injectable forms of Aripiprazole to avoid this phenomenon.
INTERNATIONAL CLINICAL PSYCHOPHARMACOLOGY
(2023)
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)
Article
Biology
Rachel E. Hardy, Injae Chung, Yizhou Yu, Samantha H. Y. Loh, Nobuhiro Morone, Clement Soleilhavoup, Marco Travaglio, Riccardo Serreli, Lia Panman, Kelvin Cain, Judy Hirst, Luis M. Martins, Marion MacFarlane, Kenneth R. Pryde
Summary: Antipsychotic drugs, including the newer generation ones, can induce mitochondrial toxicity that leads to movement disorders. It is important to understand the underlying mechanisms to minimize these adverse effects.
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
Multidisciplinary Sciences
Geng Chen, Jun Xu, Asuka Inoue, Maximilian F. Schmidt, Chen Bai, Qiuyuan Lu, Peter Gmeiner, Zheng Liu, Yang Du
Summary: This study reports two structures of the human GPR88-Gi complex, revealing an allosteric ligand involved in the interaction between the receptor and G-protein, and a potential endogenous ligand of GPR88.
NATURE COMMUNICATIONS
(2022)
Article
Chemistry, Multidisciplinary
Christoph M. Schuesslbauer, Marcel Krug, Tobias Ullrich, Hannah M. Franklin, Steven Stevenson, Timothy Clark, Dirk M. Guldi
Summary: This study reports the photophysical characterization of empty-caged, tubular fullerenes D-5h-C-90 and D-5d-C-100 and compares their properties. It found that D-5d-C-100 has a larger optical band gap and luminesces at room temperature, while D-5h-C-90 does not luminesce. The study also discovered that D-5d-C-100 undergoes hole transfer with electron-donating triethylamines but not electron transfer with electron-accepting methyl viologens.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Chemistry, Physical
Matthias Hennemann, Timothy Clark
Summary: A modified neglect of differential overlap theory was used to parameterize water and its oligomers, with the addition of polarization functions, Feynman dispersion, and a slight modification of hydrogen nucleus treatment. The results demonstrated the feasibility of obtaining accurate geometries and energies for hydrogen-bonded water aggregates.
JOURNAL OF CHEMICAL PHYSICS
(2023)
Article
Chemistry, Medicinal
Johannes Koeckenberger, Oliver Fischer, Andreas Konopa, Sebastian Bergwinkl, Susanne Muehlich, Peter Gmeiner, Roger Jan Kutta, Harald Huebner, Max Keller, Markus R. Heinrich
Summary: Two novel tool compounds, OFH5503 and OFH611, have been developed by linking fluorescent dyes and muscarinergic M-3 receptor ligands. These conjugates can be useful tools for determining binding affinities and studying receptor expression.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Jun Xu, Qinggong Wang, Harald Huebner, Yunfei Hu, Xiaogang Niu, Haoqing Wang, Shoji Maeda, Asuka Inoue, Yuyong Tao, Peter Gmeiner, Yang Du, Changwen Jin, Brian K. Kobilka
Summary: In this study, the authors used cryo-EM and NMR to investigate the mechanisms underlying the signaling versatility of M2R. They found that acetylcholine stabilizes a more heterogeneous M2R-G-protein complex than iperoxo, and LY2119620 modulates agonist efficacy in G-protein and beta-arrestin pathways differently. These findings highlight the importance of conformational dynamics in the complex signaling behavior of GPCRs.
NATURE COMMUNICATIONS
(2023)
Article
Chemistry, Medicinal
Jacqueline C. Calderon, Passainte Ibrahim, Dorothea Gobbo, Francesco Luigi Gervasio, Timothy Clark
Summary: We propose a metadynamics protocol to characterize the activation free-energy profiles of G-protein coupled receptors, focusing on the 5HT1A-receptor as a proof-of-principle study. By using the A100 activation index based on inter-helix distances, we perform metadynamics simulations and obtain free-energy profiles for the receptor in various complexes. Our results not only agree with previous experimental and computational data, but also provide detailed insights into the differences between active and inactive conformations and the role of microswitches in the activation mechanism.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Medicinal
Lukas Waterloo, Harald Hubner, Fabrizio Fierro, Tara Pfeiffer, Regine Brox, Stefan Loeber, Dorothee Weikert, Masha Y. Niv, Peter Gmeiner
Summary: The TAS2R14 receptor, found in the tongue, human airway smooth muscle, and other tissues, is a potential target for asthma and chronic obstructive pulmonary disease treatment. By modifying the structure of flufenamic acid, we developed a set of promising TAS2R14 agonists, particularly ligand 28.1, which showed higher potency and selectivity compared to flufenamic acid and other taste receptors.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Henrik Gotfredsen, Dominik Thiel, Phillip M. Greibel, Lan Chen, Marcel Krug, Ilias Papadopoulos, Michael J. Ferguson, Mogens Brondsted Nielsen, Tomas Torres, Timothy Clark, Dirk M. Guldi, Rik R. Tykwinski
Summary: This study investigates the influence of sensitizer-chromophore geometry on the separation of singlet excited states into triplet excited states. Two conjugates with different arrangements were synthesized and compared. The results show that the energy transfer rate is 26 times faster in the peripheral arrangement, even though the chromophores are farther apart. This rate acceleration is attributed to the more favorable relative orientation of the transition dipole moments in the peripheral structure. These findings are of significant importance for solar energy research.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Chemistry, Medicinal
Fabian Grassl, Leonard Bock, Alvaro Huete-Huerta Gonzalez, Martin Schiller, Peter Gmeiner, Joerg Koenig, Martin F. Fromm, Harald Huebner, Markus R. Heinrich
Summary: Based on APH199, two novel groups of D-4 subtype selective ligands were designed and evaluated, showing bias toward G(i) signaling pathway over β-arrestin recruitment compared to quinpirole. These compounds exhibited different bias profiles in terms of efficacy, potency, and GRK2 dependency, ranging from 1 to over 300 bias factors and activation from 15% to over 98% compared to quinpirole. Docking studies provided insights into the role of ECL2 and EPB in bias emergence, utilizing the diversity of functionally selective D-4 agonists.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Yifan Bo, Yuxuan Hou, Dominik Thiel, Renee Weiss, Timothy Clark, Michael J. Ferguson, Rik R. Tykwinski, Dirk M. Guldi
Summary: This study designs two tetracene dimers with different linking modes, and characterizes the interplay between intramolecular singlet fission (intra-SF) and intramolecular triplet-triplet annihilation up-conversion (intra-TTA-UC) through steady-state and time-resolved absorption and fluorescence spectroscopy. By using Pd-phthalocyanine as a sensitizer, intra-TTA-UC is achieved in the two dimers via indirect photoexcitation in the near-infrared part of the solar spectrum. Temperature-dependent measurements reveal the impact of thermal effects on intra-SF and intra-TTA-UC in different dimers.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Chemistry, Medicinal
Lukas Waterloo, Harald Huebner, Fabrizio Fierro, Tara Pfeiffer, Regine Brox, Stefan Loeber, Dorothee Weikert, Masha Y. Niv, Peter Gmeiner
Summary: TAS2R14 is a bitter taste receptor found in multiple locations, including the tongue and human airway smooth muscle. Activation of TAS2R14 can lead to bronchodilation, making it a potential target for treating asthma or chronic obstructive pulmonary disease. By modifying the structure of flufenamic acid, a study identified a group of effective and potent TAS2R14 agonists called 2-aminopyridines with a tetrazole unit. The most potent ligand, 28.1, showed a six-fold higher potency than flufenamic acid and demonstrated selectivity over other human taste receptors.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Organic
Jacqueline C. Calderon, Alberto Herrera, Frank W. Heinemann, Jens Langer, Anthony Linden, Ahmed Chelouan, Alexander Grasruck, Rafael Anez, Timothy Clark, Romano Dorta
Summary: The inversion barriers Delta G double dagger for planar chiral phosphine-alkene and sulfonamide-alkene hybrid ligands based on phenyl-dibenz-[b,f]-azepine have been determined by density-functional theory calculations. Analysis of the structural and electronic characteristics of the minima and transition states explains the magnitudes of Delta G double dagger and the geometrical changes during the inversion process. The steric repulsion caused by bulky substituents attached to the azepine nitrogen atom has a pronounced effect on the Delta G double dagger value, explaining the stereochemical stability of the ligands.
JOURNAL OF ORGANIC CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Wiebke Zika, Andreas Hirsch, Rene Weiss, Simone Pinter, Christoph M. Schuesslbauer, Timothy Clark, Andreas Hirsch, Dirk M. Guldi
Summary: This study investigates the interconversion between QC and NBD and their application in energy storage through photo-assays. An oxidative electron transfer is observed during the QC-to-NBD isomerization using transient absorption spectroscopy. The complementary use of time-resolved and steady-state spectroscopies allows for a complete description of the photoisomerization reaction of NBDs.
Article
Chemistry, Physical
Timothy Clark, Peter Politzer, Jane S. Murray
Summary: This article addresses the long-standing controversy over the physical origin of covalent bonding, concluding that both a lowering of potential energy and a lowering of kinetic energy contribute to bond formation. Using the virial theorem and analyzing changes in potential and kinetic energy as atoms approach each other, it is found that at large separations, kinetic energy decreases while potential energy increases. However, as atoms approach their equilibrium separation, these changes rapidly reverse, resulting in a net positive kinetic energy and net negative potential energy at equilibrium. Ultimately, bonding at equilibrium is solely determined by the potential energy and is electrostatic in nature.
PHYSICAL CHEMISTRY CHEMICAL PHYSICS
(2022)
Article
Chemistry, Multidisciplinary
Ilias Papadopoulos, David Gutierrez-Moreno, Yifan Bo, Ruben Casillas, Phillip M. Greissel, Timothy Clark, Fernando Fernandez-Lazaro, Dirk M. Guldi
Summary: In this study, a series of phenylene- and naphthalene-linked dimers were designed and synthesized to investigate the inherent differences in monoimide and diimide perylenes and their impact on singlet fission. The results showed that using naphthalene spacers improves the triplet quantum yield and singlet fission performance of both monoimide and diimide perylene derivatives.