Article
Biochemistry & Molecular Biology
Qi Mao, Bingjie Zhang, Sheng Tian, Wangzhi Qin, Jiaojiao Chen, Xi-Ping Huang, Ye Xin, Huicui Yang, Xue-Chu Zhen, Wenqing Shui, Na Ye
Summary: The concept of subtype selectivity and functional bias has had a significant impact on GPCR drug discovery. Through synthesis and evaluation, a series of new N-H aporphines were found to be potent and selective 5-HT2C receptor agonists. These agonists with an exclusive bias towards Gq signaling have the potential to be valuable pharmacological tools for understanding therapeutically relevant 5-HT2C signaling pathways and developing alternative antipsychotic medications.
BIOORGANIC CHEMISTRY
(2022)
Review
Nutrition & Dietetics
Edmund Przegalinski, Kacper Witek, Karolina Wydra, Jolanta H. Kotlinska, Malgorzata Filip
Summary: Obesity is a significant health and economic issue, and the serotonin system, specifically the 5-HT2C receptors, plays a crucial role in regulating body weight. This review focuses on the use of 5-HT2C receptor agonists as antiobesity medications, such as fenfluramines, sibutramine, and lorcaserin, and discusses the potential of 5-HT2C receptor positive allosteric modulators as safer alternatives. More research is needed to determine the efficacy of these drugs in obesity prevention and treatment.
Article
Chemistry, Medicinal
Stefano Tomassi, Marilisa Pia Dimmito, Minying Cai, Antonia D'Aniello, Alessandra Del Bene, Anna Messere, Zekun Liu, Tingyi Zhu, Victor J. Hruby, Azzurra Stefanucci, Sandro Cosconati, Adriano Mollica, Salvatore Di Maro
Summary: Melanocortin receptors play a pleiotropic role in various physiological and pathological processes. Scientists have developed synthetic agonists/antagonists with improved potency and selectivity by replacing the lactam cyclization of melanotan II (MT-II) with different xylene-derived thioethers. The newly designed peptides showed affinity towards melanocortin receptors within a certain range, indicating a correlation with the explored linkers. Compound 5 exhibited remarkable functional selectivity towards one of the melanocortin receptors. Molecular dynamics simulations and cryogenic electron microscopy receptor structure provided insights into the conformational behavior and affinity of the peptides.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Dylan Scott Eiger, Noelia Boldizsar, Christopher Cole Honeycutt, Julia Gardner, Stephen Kirchner, Chloe Hicks, Issac Choi, Uyen Pham, Kevin Zheng, Anmol Warman, Jeffrey Smith, Jennifer Zhang, Sudarshan Rajagopal
Summary: Some GPCR ligands can selectively activate specific signaling transducers, and this biased signaling is influenced by differential subcellular signaling of the GPCR CXC chemokine receptor 3 (CXCR3). The trafficking of CXCR3 from the plasma membrane to endosomes results in ligand-specific changes in signaling profile. Endosomal signaling is critical for biased activation of G proteins, beta-arrestins, and extracellular-signal-regulated kinase (ERK).
NATURE COMMUNICATIONS
(2022)
Article
Neurosciences
Hikari Hatakama, Nozomi Asaoka, Kazuki Nagayasu, Hisashi Shirakawa, Shuji Kaneko
Summary: The study demonstrated that SSRI improved perseverative behavior in QNP-treated mice by modulating inhibitory inputs in the lateral OFC.
Article
Chemistry, Physical
Liping Fang, Shan He, Peng Yin, Ning Wang, Bin Zhang, Haixiao Jin
Summary: This study presents the design, synthesis, and evaluation of a series of novel tryptamine derivatives with 5-HT 1B R activation. Several compounds were identified as more potent 5-HT 1B R activators compared to the FDA-approved drug sumatriptan. The molecular docking results provided insights into the binding mode and interactions between the compounds and 5-HT 1B R.
JOURNAL OF MOLECULAR STRUCTURE
(2022)
Article
Biochemistry & Molecular Biology
Spencer T. Kim, Emma J. Doukmak, Michelle Shanguhyia, Dylan J. Gray, Rachel C. Steinhardt
Summary: Orthogonal recreation of the signaling profile of a chemical synapse is a current challenge in neuroscience. In this study, photocaged compounds were used to recreate the rapid rise and fall in activation at a chemical synapse. By conjugating these compounds to a subtype-selective agonist and antagonist, the bioactive drugs could be released upon illumination with specific colors of light. The kinetics of photolysis and the control of intracellular calcium flux were characterized, allowing for greater spatiotemporal control of 5-HT2C modulation.
ACS CHEMICAL NEUROSCIENCE
(2023)
Article
Chemistry, Medicinal
Christian B. M. Poulie, Eline Pottie, Icaro A. Simon, Kasper Harpsoe, Laura D'Andrea, Igor V. Komarov, David E. Gloriam, Anders A. Jensen, Christophe P. Stove, Jesper L. Kristensen
Summary: This study evaluated the biased signaling of the 5-HT2AR receptor and found that the interaction with Ser159(3x36) is crucial for signaling and efficacy. G alpha(q)-mediated signaling was more affected. These findings contribute to the development of more effective 5-HT2AR agonists.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Organic
Scott Peruski, Scott R. Gilbertson
Summary: A new synthetic approach for the serotonin 2C receptor agonist WAY-163909 is reported in this article. The approach allows the creation of WAY-163909 versions that possess a site for linker attachment without loss of agonist activity. An efficient 7-step synthesis with a 32% overall yield is described.
TETRAHEDRON LETTERS
(2022)
Article
Pharmacology & Pharmacy
Kinga Gawlinska, Dawid Gawlinski, Malgorzata Filip, Edmund Przegalinski
Summary: Recent studies have shown a relationship between maternal diet composition and the risk of mental illnesses in offspring by affecting serotonin receptors in the brain. Different maternal diets, such as high-fat, high-carbohydrate, and mixed diets, induce specific changes in 5-HT2C and 5-HT2A receptor levels in different brain regions of the offspring. Specifically, high-fat maternal diet reduces 5-HT2C receptor expression in male rats at PND 28 but increases it at PND 63 in certain brain regions.
PHARMACOLOGICAL REPORTS
(2021)
Review
Pharmacology & Pharmacy
Alena Randakova, Jan Jakubik
Summary: Cholinergic signalling disruption through muscarinic receptors is linked to various pathologies, with potential therapeutic benefits found in selective muscarinic agonists. The identical orthosteric binding site across all muscarinic receptor subtypes makes the development of affinity-based selective agonists nearly impossible. Functionally selective and biased agonists show promise for selectively targeting individual muscarinic receptor subtypes.
PHARMACOLOGICAL RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Orr Shahar, Alexander Botvinnik, Noam Esh-Zuntz, Michal Brownstien, Rachel Wolf, Amit Lotan, Gilly Wolf, Bernard Lerer, Tzuri Lifschytz
Summary: There is growing interest in the therapeutic potential of psilocybin. This study examined the role of different serotonergic receptors and TAAR1 in modulating the head twitch response induced by 5-HTP and psilocybin in mice. The findings suggest that compounds that modulate psychedelic-induced head twitch response may have important therapeutic potential.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Chemistry, Medicinal
Jianping Chen, Erik J. Garcia, Christina R. Merritt, Joshua C. Zamora, Andrew A. Bolinger, Konrad Pazdrak, Susan J. Stafford, Randy C. Mifflin, Eric A. Wold, Christopher T. Wild, Haiying Chen, Noelle C. Anastasio, Kathryn A. Cunningham, Jia Zhou
Summary: In this study, novel oleamide analogues were designed and synthesized as selective 5-HT2CR agonists or dual 5-HT2CR/5-HT2AR positive allosteric modulators using a fragment-based discovery approach. Compound 13 (JPC0323) showed on-target properties, acceptable plasma exposure and brain penetration, and negligible displacement to orthosteric sites of over 50 GPCRs and transporters. Moreover, compound 13 suppressed novelty-induced locomotor activity in a 5-HT2CR-dependent manner, indicating 5-HT2CR agonist activity at the whole organism level at the employed doses of 13. This research discovered new selective 5-HT2CR agonists and first-in-class 5-HT2CR/5-HT2AR dual positive allosteric modulators, expanding the pharmacological toolbox for exploring the biology of these important receptors.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Gangireddy Sujeevan Reddy, Rajamanikkam Kamaraj, Kazi Amirul Hossain, Jetta Sandeep Kumar, B. Thirupataiah, Raghavender Medishetti, N. Sushma Sri, Parimal Misra, Manojit Pal
Summary: A series of novel Schiff bases designed as potential agonists of 5-HT2C receptor were synthesized and tested for their activity, with compounds 3b and 3i identified as the most active and promising candidates for further study.
BIOORGANIC CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Michelle Yen, Junming Ren, Qingxiang Liu, Caleb R. Glassman, Timothy P. Sheahan, Lora K. Picton, Fernando R. Moreira, Arjun Rustagi, Kevin M. Jude, Xiang Zhao, Catherine A. Blish, Ralph S. Baric, Leon L. Su, K. Christopher Garcia
Summary: This study presents a strategy to discover cytokine surrogate agonists by using modular ligands that exploit induced proximity and receptor dimer geometry as pharmacological metrics. The researchers generated combinatorial matrices of single-chain bispecific ligands and discovered that this approach can lead to the engineering of surrogate ligands that compel assembly of non-natural receptor heterodimers. The findings demonstrate the generalizability of this approach for the discovery of diversified agonists for various ligand-receptor systems.
Article
Multidisciplinary Sciences
Reed M. Stein, Hye Jin Kang, John D. McCorvy, Grant C. Glatfelter, Anthony J. Jones, Tao Che, Samuel Slocum, Xi-Ping Huang, Olena Savych, Yurii S. Moroz, Benjamin Stauch, Linda C. Johansson, Vadim Cherezov, Terry Kenakin, John J. Irwin, Brian K. Shoichet, Bryan L. Roth, Margarita L. Dubocovich
Editorial Material
Multidisciplinary Sciences
Brian Krumm, Bryan L. Roth
Article
Neurosciences
Yuji Nagai, Naohisa Miyakawa, Hiroyuki Takuwa, Yukiko Hori, Kei Oyama, Bin Ji, Manami Takahashi, Xi-Ping Huang, Samuel T. Slocum, Jeffrey F. DiBerto, Yan Xiong, Takuya Urushihata, Toshiyuki Hirabayashi, Atsushi Fujimoto, Koki Mimura, Justin G. English, Jing Liu, Ken-ichi Inoue, Katsushi Kumata, Chie Seki, Maiko Ono, Masafumi Shimojo, Ming-Rong Zhang, Yutaka Tomita, Jin Nakahara, Tetsuya Suhara, Masahiko Takada, Makoto Higuchi, Jian Jin, Bryan L. Roth, Takafumi Minamimoto
NATURE NEUROSCIENCE
(2020)
Article
Biochemistry & Molecular Biology
Xi-Ping Huang, Terrence P. Kenakin, Shuo Gu, Brian K. Shoichet, Bryan L. Roth
Article
Biochemistry & Molecular Biology
Kuglae Kim, Tao Che, Ouliana Panova, Jeffrey F. DiBerto, Jiankun Lyu, Brian E. Krumm, Daniel Wacker, Michael J. Robertson, Alpay B. Seven, David E. Nichols, Brian K. Shoichet, Georgios Skiniotis, Bryan L. Roth
Article
Chemistry, Medicinal
Wenwen Duan, Ying Sun, Meng Wu, Zhiyuan Zhang, Taotao Zhang, Huan Wang, Fei Li, Lingyun Yang, Yueming Xu, Zhi-Jie Liu, Tian Hua, Hong Nie, Jianjun Cheng
Summary: The study focused on designing and synthesizing novel cannabinoids based on the structural backbones of THC and CBD, showing improved metabolic stability and good in vivo pharmacokinetic profiles. Compounds 15b and 38b exhibited significant alleviation of experimental autoimmune encephalomyelitis in mice, indicating potential therapeutic effects.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(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
Wenzhong Yan, Lijun Ling, Yiran Wu, Kexin Yang, Ruiquan Liu, Jinfeng Zhang, Simeng Zhao, Guisheng Zhong, Suwen Zhao, Hualiang Jiang, Chengying Xie, Jianjun Cheng
Summary: Adenosine serves as an immunosuppressive factor in the tumor microenvironment by activating the A(2A) adenosine receptor. Dual-acting compounds targeting A(2A)R and HDAC are potentially effective immunotherapeutic agents that show promising antitumor activity in vitro and in vivo.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Neurosciences
Zhangcheng Chen, Luyu Fan, Huan Wang, Jing Yu, Dengyu Lu, Jianzhong Qi, Fen Nie, Zhipu Luo, Zhen Liu, Jianjun Cheng, Sheng Wang
Summary: Third-generation antipsychotic drugs (TGAs) have unique pharmacological properties that can improve cognition and potential antidepressant effects by targeting dopamine and serotonin receptors. By analyzing the structures of TGAs and 5-HT2AR, novel drugs with potent antipsychotic, antidepressant, and cognitive-enhancing properties can be designed.
NATURE NEUROSCIENCE
(2022)
Article
Chemistry, Medicinal
Xiaoke Gu, Haoxing Yuan, Wenchao Zhao, Nan Sun, Wenzhong Yan, Chunyu Jiang, Yan He, Hongli Liu, Jianjun Cheng, Dong Guo
Summary: This study aimed to design a photoswitchable ligand for precise control of ligand-receptor residence time and its pharmacological activity.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Ruiquan Liu, Jianzhong Qi, Huan Wang, Luyu Fan, Pei Zhang, Jing Yu, Liang Tan, Sheng Wang, Jianjun Cheng
Summary: Designed ligands of G protein-coupled receptors can have various modulating effects, including full agonist, partial agonist, antagonist, and inverse agonist. Partial agonist activity is the pharmacological feature of third-generation antipsychotics for the dopamine D2 receptor (D2R). A series of D2R partial agonists were designed and synthesized based on a benzofuran-derived D2R full agonist. Compound 10b showed excellent activity, and further optimizations led to the discovery of brain-penetrant compounds 29c and 29d with potent antipsychotic effects.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Jinfeng Zhang, Dandan Feng, Jianjun Cheng, Kurt Wuthrich
Summary: The binding affinity of G protein-coupled receptor (GPCR) ligands is usually measured by radio-ligand competition experiments. Alternatively, F-19 nuclear magnetic resonance spectroscopy (F-19-NMR) is used for screening small-molecule lead compounds in drug discovery. A fluorine-containing probe molecule, FPPA, was designed based on the structure of the A(2A) adenosine receptor (A(2A)AR) complex with V-2006. The F-19-NMR with FPPA is a robust approach for discovering ligands with new core structures.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Chemistry, Medicinal
Jianhang Mao, Yilong Cui, Huan Wang, Wenwen Duan, Zhi-Jie Liu, Tian Hua, Ning Zhou, Jianjun Cheng
Summary: This study optimized the GPR139 agonist TAK-041 and synthesized new compounds, evaluating their activity at the GPR139 receptor. The compounds showed potential therapeutic effects on schizophrenia symptoms in murine models. Compound 20a exhibited the best activity and pharmacokinetic properties, making it a promising candidate as an antischizophrenia drug.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Xiaoke Gu, Haoxing Yuan, Wenchao Zhao, Nan Sun, Wenzhong Yan, Chunyu Jiang, Yan He, Hongli Liu, Jianjun Cheng, Dong Guo
Summary: This article introduces a method for controlling the residence time of a ligand with its receptor using photo-switching technology. The researchers designed a photo-switchable ligand targeting the vasopressin V2 receptor, which can prolong the binding time with the receptor upon irradiation. The experimental results show that this photo-switchable ligand can have different inhibitory effects on cellular function and exhibits different efficacy in inhibiting renal cystogenesis both in vitro and in vivo.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Joshua Pottel, Duncan Armstrong, Ling Zou, Alexander Fekete, Xi-Ping Huang, Hayarpi Torosyan, Dallas Bednarczyk, Steven Whitebread, Barun Bhhatarai, Guiqing Liang, Hong Jin, S. Nassir Ghaemi, Samuel Slocum, Katalin V. Lukacs, John J. Irwin, Ellen L. Berg, Kathleen M. Giacomini, Bryan L. Roth, Brian K. Shoichet, Laszlo Urban