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September 2022 "The diamondback moth (Plutella xylostella) is one of the most destructive lepidopteran pests of cruciferous vegetables, and insights into regulation of its physiological processes contribute towards the development of new pesticides against it. Thus, we investigated the regulatory functions of its β-adrenergic-like octopamine receptor (PxOctβ3). The open reading frame (ORF) of PxOctβ3 was phylogenetically analyzed, and the levels of expression of the receptor mRNA were determined. This ORF was also cloned and expressed in HEK-293 cells. A series of octopamine receptor agonists and antagonists were tested against PxOctβ3. We showed that the receptor is a member of the Octβ3 protein family, and an analysis using quantitative PCR showed that it was expressed at all developmental stages of P. xylostella. Octopamine activated PxOctβ3, resulting in increased levels of intracellular cAMP. Furthermore, the agonists naphazoline, clonidine, 2-phenethylamine, and amitraz activated the PxOctβ3 receptor, and naphazoline was the most effective. Only metoclopramide and mianserin had significant antagonistic effects on PxOctβ3, whereas yohimbine, phentolamine, and chlorpromazine lacked obvious antagonistic effects. The injection of double-stranded RNA in an RNA interference assay indicated that PxOctβ3 regulates development in P. xylostella. This study demonstrated the pharmacological properties and functions of PxOctβ3 in P. xylostella, thus, providing a theoretical basis for the design of pesticides that target octopamine receptors." Read more at the source #DrGPCR #GPCR #IndustryNews

Principles of Pharmacology in Drug Discovery II - Advanced Methods for the Optimization of Candidate Binding of Stalk-derived Peptide Agonists GPCR Binders, Drugs, and more In silico exploration of 4(α-l-rhamnosyloxy Dynamic nature of G-protein coupled receptors Septerna Secures $150 Million in Series B Financing to Advance

The blood-brain-barrier (BBB) and the complexity of the central nervous system (CNS) pose a challenge for developing successful therapeutics , particularly for neurological disorder and neurodegenerative diseases. This includes diseases such as depression, Parkinson’s, schizophrenia, and Alzheimer’s. GPCRs play a central role in neuronal signaling and have been used to treat these diseases with varying degrees of success. They mediate the effects of neurotransmitters and neuromodulators. The central role of GPCRs in Neurological Disorders GPCRs are the largest family of membrane receptors and participate in several CNS functions. Most of these are essential processes, such as neurotransmission, synaptic plasticity, mood, cognition, motor control and sensory perception. Thus, they also participate in numerous diseases. Over 30% of FDA-approved drugs target GPCRs, with many targeting CNS located GPCRs. Most of them are small molecules capable of going through the BBB , and since their targets are on the membrane of cells, they have easier access to the receptors than those that need to get into the cells to modulate intracellular signaling. One of the biggest hurdles is the understanding and correct targeting of the different receptor subtypes involved in each disease and the downstream and side effects attached to them. GPCR Structure, Activation, and Signaling Pathways in the Brain An understanding of GPCR structure is key in drug design. GPCRs posses a seven-transmembrane domain architecture, which lets them transduce extracellular signals into intracellular responses. They manage this by interacting with G-proteins. What happens when a GPCR is activated? When the endogenous binder of the GPCR (which can be a neuromodulator, neurotransmitter, etc.), binds to the extracellular binding site of the GPCR, the protein changes into its active conformation , which starts the intracellular signaling cascade. Depending on the type of GPCR, it can lead to different secondary messengers , like cAMP, IP3, which will ultimately modify gene expression, neurotransmitter release and plasticity. Figure 1. GPCR signaling: (A) an orthosteric ligand (orange) binds an inactive GPCR, the β2 adrenergic receptor (β2AR; PDB ID: 2RH1); (B) A ligand-bound GPCR undergoes a conformational change to its active state (PDB ID: 3SN6); and (C) an active GPCR binds a G protein (PDB ID: 3SN6), which subsequently promotes nucleotide release from, and activation of, the G protein α-subunit. Source: Latorraca NR, Venkatakrishnan AJ, Dror RO. GPCR Dynamics: Structures in Motion. Chem Rev. 2017 Jan 11;117(1):139-155. The activation of these pathways regulates pain modulation, memory consolidation, motor coordination etc. The concept of biased agonism must also be highlighted here. The conformation change induced by the agonist may not always lead to the same intracellular signaling . Some agonists induce conformations more adept at activating β-arrestins for example, leading to different intracellular effects. Studying these routes may reduce side-effects when using GPCR-based therapies. Emerging GPCR Therapeutic Targets in CNS Drug Discovery GPCRs have been studied for decades, but there are some, known as orphan GPCRs , which seem to be implicated in CNS pathologies but are not fully studied. Some of these are GPR6, GPR37 and GPR139 , which participate in motor control, neuroprotection and metabolic regulation. Their physiological ligands are not fully understood, which opens new treatment possibilities. GPR6 has been linked to neuroprotective functions and is now being investigated for its role in Parkinson’s disease and neuropathic pain. GPR37 has been linked to the Parkinson’s disease as well, though more focused on the progression of the disease. GPR139 is implicated in schizophrenia and ADHD. Figure 2. Orphan GPCRs related to neurodegenerative disorders. Source: Kim J, Choi C. Orphan GPCRs in Neurodegenerative Disorders: Integrating Structural Biology and Drug Discovery Approaches. Curr Issues Mol Biol. 2024 Oct 19;46(10):11646-11664. Of the traditional GPCRs, CBRs are gaining ground as potential therapeutic targets in several CNS diseases, such as Parkinson’s. As mentioned in previous posts, CELT-335, one of our fluorescent compounds, was successfully employed in a binding assay for CB1R and CB2R. More research into the endocannabinoid system (ECS) will let us access these GPCRs in a safer manner. Both orphan and well-characterized GPCRs are untapped opportunities for drug development targeting CNS diseases , especially as traditional targets seem to have stagnated when not focusing on biased-agonism. The newer generations of targets and screening tools will pave the way for safer and more efficient drugs. Advantages of Fluorescent Ligands in GPCR Drug Screening for CNS Choosing the right tools is important for the success of drug discovery, just as much as choosing the right targets. One of the best tools to study therapeutic targets are fluorescent ligands , which are very useful in GPCR drug discovery, starting from hit and lead validation all the way to pre-clinical assays. Some of the advantages of using fluorescent ligands for this are: Live-cell imaging:  receptor-ligand interactions can be visualized in real-time without fixating the cells. Greater specificity : allows for selective tracking of receptor subtypes in complex brain tissues. Reduced background noise: Improvements in signal-to-noise ratio are key in CNS assays. Faster assay development: also speeds GPCR target validation. Avoid safety concerns and regulatory hurdles: Non-radioactive alternative to screening In the context of CNS drug development, where receptor localization and real-time signaling are crucial , fluorescent ligands offer a powerful and adaptable solution. Their integration into drug discovery neuroscience workflows helps accelerate GPCR target identification, characterization, and lead optimization. References Latorraca NR, Venkatakrishnan AJ, Dror RO. GPCR Dynamics: Structures in Motion . Chem Rev. 2017 Jan 11;117(1):139-155. doi: 10.1021/acs.chemrev.6b00177 Alavi MS, Shamsizadeh A, Azhdari-Zarmehri H, Roohbakhsh A. Orphan G protein-coupled receptors: The role in CNS disorders . Biomed Pharmacother. 2018 Feb;98:222-232. doi: 10.1016/j.biopha.2017.12.056 Azam S, Haque ME, Jakaria M, Jo SH, Kim IS, Choi DK. G-Protein-Coupled Receptors in CNS: A Potential Therapeutic Target for Intervention in Neurodegenerative Disorders and Associated Cognitive Deficits . Cells. 2020 Feb 23;9(2):506. doi: 10.3390/cells9020506   Kim J, Choi C. Orphan GPCRs in Neurodegenerative Disorders: Integrating Structural Biology and Drug Discovery Approaches. Curr Issues Mol Biol. 2024 Oct 19;46(10):11646-11664. doi: 10.3390/cimb46100691   Navarro G, Sotelo E, Raïch I, Loza MI, Brea J, Majellaro M. A Robust and Efficient FRET-Based Assay for Cannabinoid Receptor Ligands Discovery. Molecules. 2023 Dec 15;28(24):8107. doi: 10.3390/molecules28248107

Contest Committee Sponsors GPCR Retreat Program < Back to schedule Cannabinoid compounds to augment L-DOPA

Daniel Kahne and Suzanne Walker studying the structure and function of the essential human enzyme, O-GlcNAc Olympiad Journey John shared his experiences in high school, where he developed a keen interest in advanced Journey John shared his experience with the Chemistry Olympiad program, highlighting its rigorousness and advanced Scientific Journey and Lab Collaboration John discussed his scientific journey, starting with a project in Suzanne He then moved to Dan's lab where he met Suzanne and her project.

Advanced data analysis for GPCR pharmacology Dr.