Article
Biochemistry & Molecular Biology
Sanda Nastasia Moldovean, Diana-Gabriela Timaru, Vasile Chis
Summary: The D2 dopamine receptor plays a crucial role in modulating dopamine release and radiopharmaceutical ligands are used to quantify dopaminergic pathways in the living human brain. This study used molecular dynamics simulations and QM calculations to investigate the interaction mechanisms and binding affinities between three synthetic compounds and the D2 receptor.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Kwabena Owusu Dankwah, Jonathon E. Mohl, Khodeza Begum, Ming-Ying Leung
Summary: This study computationally predicted the binding of a single ligand to GPCRs from different families and uncovered similar binding pockets that contribute to ligand interactions. These findings can be applied to improve protein function inference, drug repurposing, drug toxicity prediction, and the acceleration of new drug development.
Article
Biochemistry & Molecular Biology
Lukas Zell, Alina Bretl, Veronika Temml, Daniela Schuster
Summary: Different dopamine receptor subtypes are involved in various conditions, and this study identified novel ligands with high affinity and selectivity for D2R/D3R. In vitro experiments and in silico analysis were used to rationalize the ligands' selectivity and interaction with secondary binding pockets. This research contributes to the understanding of structural motifs responsible for DR subtype selectivity and can aid drug development in D2R/D3R-associated pathologies.
Article
Biochemistry & Molecular Biology
Attila Egyed, Adam A. Kelemen, Marton Vass, Andras Visegrady, Stephanie A. Thee, Zhiyong Wang, Chris de Graaf, Jose Brea, Maria Isabel Loza, Rob Leurs, Gyorgy M. Keseru
Summary: Recent structural studies have identified several allosteric sites for pharmacological intervention in addition to the orthosteric binding pockets of GPCRs. Through a virtual screening protocol, new bitopic compounds targeting specific receptor profiles were designed. The designed compounds showed biased selectivity towards the desired receptor targets and successfully addressed limitations of known drugs.
BIOORGANIC CHEMISTRY
(2021)
Article
Pharmacology & Pharmacy
Yarim Elideth De la Luz-Cuellar, Ulises Coffeen, Francisco Mercado, Vinicio Granados-Soto
Summary: This study investigated the impact of sex on the antiallodynic activity of spinal dopamine D1 and D2-like receptors in a model of fibromyalgia-type pain in rats. The results showed that drugs targeting these receptors had a greater effect on female rats compared to male rats. Sex differences were also observed in a nerve injury model. These findings suggest that the antiallodynic effect of dopamine receptors in fibromyalgia-type pain is influenced by hormonal receptors.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2023)
Article
Pharmacology & Pharmacy
B. F. G. Queiroz, F. C. S. Fonseca, R. C. M. Ferreira, T. R. L. Romero, A. C. Perez, I. D. G. Duarte
Summary: This study investigated the role of dopamine and its receptors in the peripheral processing of the nociceptive response in mice using a pharmacological approach and the paw pressure test. The results showed that dopamine at small doses produced antinociceptive effects via the activation of D-2-like receptors, while at higher doses it caused hyperalgesia via the activation of D-1-like receptors.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2022)
Article
Multidisciplinary Sciences
J. D. Gross, D. W. Kim, Y. Zhou, D. Jansen, L. M. Slosky, N. B. Clark, C. R. Ray, X. Hu, N. Southall, A. Wang, X. Xu, E. Barnaeva, W. C. Wetsel, M. Ferrer, J. J. Marugan, M. G. Caron, L. S. Barak, K. Toth
Summary: This study discovered a novel GHSR(1a) agonist called N8279, which exhibits strong selectivity for G protein signaling, providing potential for treating disorders of disrupted dopamine homeostasis.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Biochemistry & Molecular Biology
Boeun Lee, Michelle Taylor, Suzy A. Griffin, Tamara McInnis, Nathalie Sumien, Robert H. Mach, Robert R. Luedtke
Summary: The study showed that N-phenylpiperazine analogs can selectively bind to the human D3 dopamine receptor with significant D3 vs. D2 binding selectivity, potentially leading to the development of pharmacotherapeutics for levodopa-induced dyskinesia in patients with Parkinson's disease.
Article
Biochemistry & Molecular Biology
Daiki Masukawa, Satoshi Kitamura, Rei Tajika, Hiraku Uchimura, Masami Arai, Yuuki Takada, Tetsu Arisawa, Momoyo Otaki, Kaori Kanai, Kenta Kobayashi, Tomoyuki Miyazaki, Yoshio Goshima
Summary: Dopamine (DA) is involved in neurological and physiological functions such as motor control. L-3,4-dihydroxyphenylalanine (L-DOPA), traditionally seen as an inert precursor of DA, is now shown to be a neurotransmitter itself.
JOURNAL OF NEUROCHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Vanessa Boritzki, Harald Hubner, Anni Allikalt, Peter Gmeiner, Birgitta M. Wohrl
Summary: The study focused on expressing human dopamine receptors D-2S and D-3 in Escherichia coli using different fusion proteins and mutations to optimize expression and evaluate ligand binding. Results showed that the presence of a C-terminal fusion protein, but not the type, is important for receptor expression. Improved receptor variants with high affinity ligand binding can be selected using FACS analysis and error-prone PCR.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Martin Nagl, Denise Moennich, Niklas Rosier, Hannes Schihada, Alexei Sirbu, Nergis Konar, Irene Reyes-Resina, Gemma Navarro, Rafael Franco, Peter Kolb, Paolo Annibale, Steffen Pockes
Summary: This study describes the synthesis of a set of new fluorescent ligands for visualization of dopamine D-2-like receptors. The ligand UR-MN212 (20) showed high affinity for D-2-like receptors and moderate selectivity towards D-1-like receptors. It displayed rapid association with D2longR and can be used for fluorescence microscopy studies. The ligand's binding affinity was determined in a single-digit nanomolar range, consistent with radioligand binding data.
Review
Pharmacology & Pharmacy
Hsin-Yung Yen, Ali Jazayeri, Carol Robinson
Summary: GPCRs are important drug targets due to their involvement in physiological processes. Mass spectrometry techniques, such as HDX-MS and native-MS, provide opportunities to investigate GPCR pharmacology and discover new drugs. This review highlights the potential of MS techniques for in-depth investigations of GPCR biology.
PHARMACOLOGICAL REVIEWS
(2023)
Article
Chemistry, Medicinal
Daniel Pulido, Veronica Casado-Anguera, Marc Gomez-Autet, Natalia Llopart, Estefania Moreno, Nil Casajuana-Martin, Sergi Ferre, Leonardo Pardo, Vicent Casado, Miriam Royo
Summary: This study successfully designed and synthesized heterobivalent ligands that can simultaneously bind to adenosine A(2A) receptors and dopamine D-2 receptors, and demonstrated their binding to the receptor heteromer through various experimental techniques.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Boshi Huang, Rama Gunta, Huiqun Wang, Mengchu Li, Danni Cao, Rolando E. Mendez, James C. Gillespie, Chongguang Chen, Lan-Hsuan M. Huang, Lee-Yuan Liu-Chen, Dana E. Selley, Yan Zhang
Summary: The 3-hydroxy group of epoxymorphinan derivatives plays a crucial role in their binding affinity and selectivity profiles towards opioid receptors. Molecular modeling studies help explain the differences in binding affinity and functional profiles between compounds with and without the 3-hydroxy group.
BIOORGANIC CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Thayssa Tavares da Silva Cunha, Rafaela Ribeiro Silva, Daniel Alencar Rodrigues, Pedro de Sena Murteira Pinheiro, Thales Kronenberger, Carlos Mauricio R. Sant'Anna, Francois Noel, Carlos Alberto Manssour Fraga
Summary: Most neurodegenerative diseases are multifactorial, and the molecular mechanisms related to their development are constantly advancing. Dopamine and dopaminergic receptor subtypes play a crucial role in the pathophysiology of various neurological disorders. Therefore, the dopaminergic system and dopamine receptor ligands are important for the treatment of these disorders.
Article
Biochemistry & Molecular Biology
Chia-Ju Hsieh, Aladdin Riad, Ji Youn Lee, Kristoffer Sahlholm, Kuiying Xu, Robert R. Luedtke, Robert H. Mach
Summary: [F-18]Fallypride and [F-18]Fluortriopride exhibit different properties in labeling the D3 receptor, with Fallypride able to bind under baseline conditions while FTP requires the depletion of synaptic dopamine. In silico studies suggest that FTP has a weaker interaction with the D3R's binding site compared to Fallypride, consistent with competition assay results. This study indicates the potential of in silico methods in predicting a small molecule's ability to compete with synaptic dopamine for binding to the D3R.
Article
Biochemistry & Molecular Biology
Boeun Lee, Michelle Taylor, Suzy A. Griffin, Tamara McInnis, Nathalie Sumien, Robert H. Mach, Robert R. Luedtke
Summary: The study showed that N-phenylpiperazine analogs can selectively bind to the human D3 dopamine receptor with significant D3 vs. D2 binding selectivity, potentially leading to the development of pharmacotherapeutics for levodopa-induced dyskinesia in patients with Parkinson's disease.
Article
Chemistry, Medicinal
Ho Young Kim, Ji Youn Lee, Chia-Ju Hsieh, Aladdin Riad, Nicholas J. Izzo, Susan M. Catalano, Thomas J. A. Graham, Robert H. Mach
Summary: In this study, a panel of 46 compounds with high affinity for Sigma 2 receptors was screened. Compound (+/-)-7 and its analogue (+/-)-8 showed excellent binding affinity and subtype selectivity for Sigma 2 receptors. In vitro binding experiments indicated that the binding of these compounds to Sigma 2 receptors was dependent on TMEM97 protein expression. PET studies demonstrated that compound (+/-)-7 had higher brain uptake and specific distribution in the cortex and hypothalamus compared to compound (+/-)-8. Brain uptake or tissue binding of the radiotracer was selectively inhibited by ligands with different Sigma 2 receptor binding affinities. The results suggest that compound (+/-)-7 can be used as a PET radiotracer for imaging Sigma 2 receptor function in central nervous system disorders.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Cell Biology
Robert K. Doot, Anthony J. Young, Ilya M. Nasrallah, Reagan R. Wetherill, Andrew Siderowf, Robert H. Mach, Jacob G. Dubroff
Summary: Neuroinflammation is an important factor in neurodegenerative diseases and is mediated by microglia. This study used [F-18]NOS PET imaging to measure neuroinflammation in idiopathic Parkinson's disease patients and found increased oxidative stress as a marker of inflammation in early-stage disease.
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
Chi-Chang Weng, Aladdin Riad, Brian P. Lieberman, Kuiying Xu, Xin Peng, John L. Mikitsh, Robert H. Mach
Summary: This study compares the binding affinity and effectiveness of two radioligands, [H-3]DTG and [I-125]RHM-4, in screening new sigma 2R/TMEM97 compounds. The results indicate that [I-125]RHM-4 is an improved radioligand for in vitro binding studies of sigma 2R/TMEM97.
Article
Biochemistry & Molecular Biology
Run-Duo Gao, Michelle Taylor, Tamara McInnis, Zhenglan Chen, Sadakatali S. Gori, Heather M. LaPorte, Maxime A. Siegler, Janet L. Neisewander, Robert H. Mach, Meharvan Singh, Barbara S. Slusher, Rana Rais, Robert R. Luedtke, Takashi Tsukamoto
Summary: Reduced haloperidol (1) acts as a potent S1R ligand with lower affinity to D2R and facilitates BDNF secretion. However, its therapeutic utility is limited due to oxidation back to haloperidol, which has adverse effects. A difluorinated analogue (2) was synthesized to minimize oxidation and was found to exhibit high affinity to S1R and promote BDNF release. Compound 2 distributed to the brain, reversed learning deficits, and shows promise for the treatment of cognitive impairments.
ACS CHEMICAL NEUROSCIENCE
(2023)
Article
Biochemistry & Molecular Biology
Bashar M. Thejer, Vittoria Infantino, Anna Santarsiero, Ilaria Pappalardo, Francesca S. Abatematteo, Sarah Teakel, Ashleigh Van Oosterum, Robert H. Mach, Nunzio Denora, Byung Chul Lee, Nicoletta Resta, Rosanna Bagnulo, Mauro Niso, Marialessandra Contino, Bianca Montsch, Petra Heffeter, Carmen Abate, Michael A. Cahill
Summary: Sigma-2 receptor (S2R) is functionally associated with both transmembrane protein TMEM97 and translocator protein (TSPO). This study provides evidence of the interaction between S2R and TSPO, as well as the physical colocalization of TMEM97 and TSPO in certain cancer cells. Additionally, the role of S2R-interacting partner PGRMC1 was clarified. This is the first suggestion of a functional interaction between TSPO and TMEM97, which can be influenced by S2R ligands.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Ana Maria Estrada-Sanchez, Claudia Rangel-Barajas, Andrew G. Howe, Scott J. Barton, Robert H. Mach, Robert R. Luedtke, George V. Rebec
Summary: Activation of D3 receptors delays the onset and reduces the frequency of head twitches induced by DOI. It also leads to slight changes in neuronal activity, mainly in the dorsal striatum, and increases correlated firing between cortical pyramidal neurons and striatal medium spiny neurons. These findings provide insights into the treatment of neuropathologies with involuntary movements.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Chemistry, Medicinal
Chia-Ju Hsieh, Sam Giannakoulias, E. James Petersson, Robert H. H. Mach
Summary: The use of computer-aided drug design (CADD) in radiotracer development is increasing. Traditional CADD methods, such as virtual screening and optimization, have been successfully used in drug discovery programs. This review discusses the use of virtual screening for hit identification, filtering and culling hits for in vitro assays, optimizing hit compounds for PET, and the latest techniques in CADD employing machine learning.
Article
Chemistry, Medicinal
Thomas J. A. Graham, Anton Lindberg, Junchao Tong, Jeffrey S. Stehouwer, Neil Vasdev, Robert H. Mach, Chester A. Mathis
Summary: A chemical fingerprint search revealed Z3777013540 as a potential 4R-tau binding ligand. Binding assays in AD, PSP, and CBD brain showed high affinity, with K(D) (nM) values ranging from 4.0 to 5.1. In vivo PET imaging in rats with [F-18]1 demonstrated good brain penetration and rapid clearance. Another compound, Z4169252340, showed even lower affinities for binding aggregated α-synuclein and amyloid-beta, but demonstrated higher brain penetration in PET imaging. Both compounds are expected to be useful in discovering potent 4R-tau radiotracers.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
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
Chemistry, Multidisciplinary
Marshall G. Lougee, Vinayak Vishnu Pagar, Hee Jong Kim, Samantha X. Pancoe, W. Kit Chia, Robert H. Mach, Benjamin A. Garcia, E. James Petersson
Summary: The intrinsic photochemistry of isoxazole, a common heterocycle in medicinal chemistry, can be used as an alternative to existing strategies using more perturbing, extrinsic photo-crosslinkers. The utility of isoxazole photo-crosslinking has been demonstrated in a wide range of biologically relevant experiments, including common proteomics workflows.
CHEMICAL COMMUNICATIONS
(2022)
Article
Oncology
Hsiaoju S. Lee, Sally W. Schwarz, Erin K. Schubert, Delphine L. Chen, Robert K. Doot, Mehran Makvandi, Lilie L. Lin, Elizabeth S. McDonald, David A. Mankoff, Robert H. Mach
Summary: This article describes the development of F-18-FTT as a radiotracer for imaging PARP-1 expression levels in breast and ovarian cancer patients. It also discusses the preparation and submission of an exploratory investigational new drug application to the FDA and the need for a commercialization strategy to overcome financial barriers in multicenter clinical trials.
RADIOLOGY-IMAGING CANCER
(2022)
Review
Chemistry, Medicinal
Silvio Aime, Mohammed Al-Qahtani, Martin Behe, Guy Bormans, Giuseppe Carlucci, Jean N. DaSilva, Clemens Decristoforo, Adriano Duatti, Philip H. Elsinga, Klaus Kopka, Xiang-Guo Li, Zhibo Liu, Robert H. Mach, Oskar Middel, Jan Passchier, Marianne Patt, Ivan Penuelas, Ana Rey, Peter J. H. Scott, Sergio Todde, Jun Toyohara, Danielle Vugts, Zhi Yang
Summary: The Editorial Board releases highlight commentary to update readers on trends in radiopharmaceutical development, covering 23 different topics from novel radiochemistry to first in man application of novel radiopharmaceuticals, highlighting progress in the research field.
EJNMMI RADIOPHARMACY AND CHEMISTRY
(2021)