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Targeting GPCRs in the CNS: Advances in Drug Discovery Strategies

Updated: Oct 1

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.
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.
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 

 

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