Aug 2026· European Journal of Pharmacology· Vol 1033, pp.
179275
· 0 citations· 181 references
Medicine
TL;DR
This review comprehensively examines the pathophysiological roles and therapeutic potential of GPCRs in major neurological and psychiatric disorders, including Parkinson's disease, Alzheimer's disease, multiple sclerosis, and depression, and highlights how dysregulated signaling through specific GPCRs contributes to disease pathogenesis.
Abstract
G protein-coupled receptors (GPCRs) are major therapeutic targets for central nervous system disorders, with more than 500 approved drugs targeting this receptor family worldwide. This review comprehensively examines the pathophysiological roles and therapeutic potential of GPCRs in major neurological and psychiatric disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), and depression. We highlight how dysregulated signaling through specific GPCRs, including dopamine and adenosine A2A receptors in PD, the mGlu5 receptor and muscarinic acetylcholine receptors in AD, S1P and GPR17 receptors in MS, and 5-HT1A and GPR39 receptors in depression, contributes to disease pathogenesis. Beyond canonical monomeric activation, this review emphasizes emerging concepts in GPCR heterodimerization (e.g., the 5-HT1A/orexin 1 receptor complex activating Gαs pathways), biased signaling, and allosteric modulation, which provide opportunities to develop therapeutics with greater specificity and fewer adverse effects. We also evaluate the therapeutic potential of targeting these mechanisms using specific pharmacological agents, including synthetic compounds and structurally defined natural product-derived molecules. The chemical structures of key natural products-including paeoniflorin, rosmarinic acid, and ergothioneine-are presented, with their GPCR interactions and critical pharmacophores highlighted. Finally, we discuss future directions involving advanced technologies, including cryo-electron microscopy, induced pluripotent stem cell-derived brain organoids, structural biology, and artificial intelligence, to improve understanding of complex GPCR signaling. The development of biased ligands, stage-specific interventions, and GPCR-based biomarkers represents a critical step toward personalized and more effective treatments for neurological disorders.
Alzheimer's disease (AD) is the leading cause of dementia and still lacks an effective treatment that can slow or stop disease progression. In addition to amyloid-β and tau pathology, AD involves major disturbances in calcium balance, neurotransmission, and synaptic plasticity. Conventional orthosteric drugs provide limited symptomatic benefit and often interfere with physiological receptor function, underscoring the need for more selective therapeutic strategies. This review explores allosteric modulation of neurotransmitter receptors as a potential neuroprotective strategy in AD, with an emphasis on mechanisms that restore synaptic integrity, regulate calcium homeostasis, and engage disease-relevant intracellular signaling pathways. The review synthesizes preclinical and clinical evidence on allosteric modulators targeting key ionotropic receptors, including NMDA, AMPA, GABA-A, nicotinic acetylcholine, and P2X7 receptors, and G protein-coupled receptors (GPCRs) such as M1 muscarinic receptors, metabotropic glutamate receptors, and the calcium-sensing receptor. Particular attention is given to receptor selectivity, signaling bias, and translational relevance. Allosteric modulation of ionotropic receptors can influence excitability and synaptic plasticity and may preserve endogenous neurotransmission, with circuit-stabilizing effects reported mainly in preclinical studies. GPCR-directed allosteric modulators can affect AD-related processes, including amyloid- and tau-associated toxicity, excitotoxicity, and neuroinflammation, although evidence for these effects is largely preclinical and clinical translation remains challenging. Convergent pathways, such as Ca2+-dependent signaling, ERK/CREB, PI3K/Akt, and cAMP/PKA, may represent shared mediators of disease-relevant effects. Allosteric modulation may offer a more refined, receptor-specific framework for therapeutic investigation in AD. Ionotropic and GPCR-targeted agents may each produce symptomatic or preclinical disease-relevant effects, but their capacity to slow disease progression in patients remains unproven and will require current pharmacological and translational challenges to be addressed.
A. Fereidouni, Setayesh Nematollahi, K. T. Mathew et al.· International Journal of Bio...· 0 citations
Depression is a leading cause of disability worldwide, and currently available antidepressants are limited by delayed therapeutic onset, inadequate efficacy in some patients, and adverse effects. G protein-coupled receptors (GPCRs), the largest family of membrane receptors in the central nervous system, regulate neurotransmission, neuroplasticity, neuroinflammation, stress responses, and reward processing, and are therefore important targets for antidepressant drug development. Natural products are a rich source of structurally diverse bioactive compounds, many of which show antidepressant-like effects through the modulation of GPCR-mediated signaling pathways. In this narrative review, we summarize the roles of major GPCR families implicated in depression and provide an updated overview of natural products that modulate these receptors. We particularly emphasize receptor-specific mechanisms, downstream signaling networks, and the pharmacological actions of representative natural compounds. We also highlight emerging concepts in GPCR biology, including receptor heteromerization, signaling bias, and allosteric modulation, that may create new opportunities for antidepressant discovery. Finally, we discuss current challenges related to target validation, pharmacokinetics, and clinical translation. Collectively, these insights support further investigation of natural product-derived GPCR modulators as potential leads for next-generation antidepressant development.
Hua-Yan Li, Xi-Ying He, Ting Cao et al.· Pharmaceuticals· 0 citations
The Alzheimer's Disease (AD) lacks effective disease-modifying therapy, even though amyloid-targeting immunotherapies have recently been applied clinically. N-methyl-D-Aspartate Receptors (NMDARs) play a central yet mechanistically complicated role in the pathophysiology of AD, where they are convergence points of amyloid-beta (Aβ) oligomer toxicity, tau-dependent excitotoxicity, and progressive synaptic failure. This critical review examines NMDAR dysfunction across the AD spectrum, with a focus on subunit-regulated signalling, subcellular localisation, and subsequent pathological cascades. The effects of Aβ oligomers on NMDAR activity involve multiple mechanisms that disrupt their function, including glutamate dysregulation mediated by GLT-1, redistribution of GluN2B to extrasynaptic areas, and inhibition of JAK2-CREB via activation of extrasynaptic receptors. Tau enhances excitotoxic injury throughdendritic mislocalization, and the tau-Fyn-GluN2B complex, which propels pro-death signalling by DAPK1. This conceptually important prevailing synaptic-extrasynaptic dichotomy is fiercely criticised here, given evidence that synaptic receptors containing GluN2A also mediate pathological signalling during sustained Aß exposure, and that tri-heteromeric receptor populations are problematic for subunit-selective targeting. Neuroinflammation, dysfunction of the blood-brain barrier, and excitotoxic amplification via GluN2C/D-enriched receptor pools in neurons, astrocytes, microglia, oligodendrocytes, and endothelial cells are underexplored therapeutic targets for neurodegenerative disease (non-neuronal NMDARs). Memantine is the only approved NMDAR-targeting agent for AD. Subunit-selective antagonists have not been translated into clinical use, and the positive allosteric modulator dalzanemdor (SAGE-718) did not pass its randomised Phase 2 trial in 2024. The most mechanistically justified approach is to advance subunit-selective, compartment-specific, or protein-complexdisrupting strategies. Although it is not established whether any single NMDAR-targeting intervention will suffice as a disease-modifying therapy, the convergence of molecular, genetic, and clinical evidence positions NMDAR dysfunction as a tractable , if therapeutically demanding , node in the AD pathogenic network, warranting continued, mechanism-informed drug discovery.
Md Sirajuddin Khan, A. M. Ashesh, Mithul V. Mammen et al.· Current Neuropharmacology· 0 citations
G-protein-coupled receptors (GPCRs) represent a compelling intersection of structural biology, systems pharmacology, and clinical medicine. They function as essential molecular regulators of cardiovascular physiology, governing processes from the initiation of cardiac rhythm in the sinoatrial node to the regulation of vascular tone. Their widespread expression in cardiac and vascular tissues, combined with their ability to integrate diverse extracellular signals, positions GPCRs as key regulators of heart rate, contractility, vascular tone, inflammation, and metabolic homeostasis. Recent advances in GPCR structural biology, coupled with mechanistic insights into G-protein- and β-arrestin-mediated signaling mechanisms, underscore their central role in both cardiovascular health and disease. Notably, dysregulation of GPCR signaling has emerged as a unifying mechanism across major cardiovascular diseases (CVDs), contributing to pathological remodeling, impaired contractile function, and maladaptive vascular responses. This review uniquely integrates GPCR structural biology, signaling dynamics, and mechanosensitive and biased signaling mechanisms within the cardiovascular system. We discuss the contributions of class A, class B, and other GPCR families to cardiovascular physiology and pathology emphasizing their relevance to the development of targeted interventions for hypertension, heart failure, arrhythmias, atherosclerosis, and related CVDs. Together, these insights establish a contemporary framework for advancing precision GPCR-directed therapies in CVDs. By framing these developments within a mechanistic and translational context, the review offers a timely and clinically significant resource for both basic researchers and clinicians.
Shaherin Basith, Gwang Lee· Medicinal research reviews (...· 0 citations
G protein-coupled receptors (GPCRs) signal across a continuum of activation states, yet how ligands encode distinct signaling efficacies remains poorly understood. Here, we define the molecular mechanism underlying graded activation of the dopamine D1 receptor (D1R), a major therapeutic target for neuropsychiatric disorders. Functional analyses reveal that two widely used pharmacological tools, LE300 and SCH23390, possess intrinsic efficacy as an inverse agonist and a weak partial agonist, respectively, rather than the efficacy-silent neutral antagonists. Structural, molecular dynamics and mutagenesis analyses capture previously unrecognized inactive and intermediate receptor activation states that bridge known active conformations, and reveal that ligand efficacy is encoded through the progressive engagement of a conserved activation pathway centered on the W6.48 toggle switch. Guided by this mechanism, a single chemical modification markedly increases the agonist efficacy of SCH23390. Comparison with dopamine D2 receptor structures further reveals a conserved mechanism of inverse agonism despite distinct subtype-specific recognition. Together, these findings establish a structural framework for graded agonism at D1R and provide general principles for the rational design of efficacy-tuned therapeutics at dopamine receptors and related GPCRs.
Xinyue Zhang, Yu Zheng, Heng Liu et al.· bioRxiv· 0 citations
Synaptic dysfunction is the earliest and most critical pathological feature of Alzheimer's disease (AD), directly contributing to cognitive decline. This review provides an integrative overview of the molecular and biochemical modulators governing synaptic plasticity and their disruption in AD. We discuss how the collective impairment of Aβ aggregation, tau pathology, calcium imbalance, oxidative stress, and neuroinflammation affects dendritic spine morphology and synaptic connectivity. Particular attention is given to neurotrophins such as brain-derived neurotrophic factor and TrkB signaling, hormonal influences, likewise glucocorticoids, estrogens, testosterone, endocannabinoid pathways, lipid and cholesterol regulators like ApoE and lipid rafts, and epigenetic mechanisms that modulate synaptic resilience. We further evaluate the therapeutic potential of pharmacological agents, including cholinesterase inhibitors, NMDA receptor modulators, and multi-target directed ligands alongside nutraceuticals such as resveratrol, curcumin, omega-3 fatty acids, Withania somnifera, and Bacopa monnieri. Emerging technologies, including iPSC-derived neuronal models, optogenetics, and advanced neuroimaging biomarkers like SV2A PET, cerebrospinal fluid/plasma neurogranin, are also highlighted for their role in elucidating and monitoring synaptic integrity. Ultimately, targeting the biochemical modulators of synaptic plasticity offers a promising avenue for AD therapy, especially through combinatorial and precision-medicine strategies aimed at restoring synaptic function and cognitive performance.
I. Farzeen, Muhammad Muzammil Nazir, Zunaira Jaan et al.· Journal of Alzheimer's Disea...· 0 citations
