Summary: This review focuses on biased agonism at opioid receptors as a strategy to improve pain management by overcoming the limitations of current opioid analgesics, such as tolerance, dependence, addiction, and other adverse effects. It explains that opioids act through GPCRs, and different opioid receptor subtypes (MOR, KOR, DOR, NOP) have varying therapeutic profiles and side effects. The core concept discussed is functional selectivity, where biased ligands can activate specific downstream signaling pathways, such as G-protein mediated signals, while avoiding others like β-arrestin recruitment, to achieve analgesia with reduced side effects and abuse potential. The paper aims to review the design and pharmacological outcomes of such biased ligands at opioid receptors.

Summary: This review critically assesses the hypothesis that G protein-biased agonists at the mu-opioid receptor (MOPr) offer improved analgesic profiles by separating G protein-mediated analgesia from β-arrestin-mediated side effects like respiratory depression and constipation. The authors highlight that initial evidence supporting this hypothesis, particularly from β-arrestin2-knockout mouse studies, has not been consistently reproduced, and alternative genetic models do not support the concept. Furthermore, they argue that the observed G protein bias of many developed MOPr agonists may be confounded by assay amplification, suggesting these ligands might actually be unbiased with low intrinsic efficacy. The paper concludes that current evidence does not strongly support the notion that G protein-biased MOPr agonism will yield substantially improved therapeutic profiles, proposing that low intrinsic efficacy might be an alternative mechanism for achieving wider therapeutic windows.

Summary: This paper discusses ongoing efforts to identify and characterize biased ligands specifically for opioid receptors.

Summary: This review examines biased agonism at opioid receptors, particularly the mu-opioid receptor, in the context of pain management. It highlights the initial hypothesis that selective activation of G protein-dependent signaling over beta-arrestin-dependent signaling could yield analgesia without adverse effects like respiratory depression. However, the paper notes that recent data suggest both therapeutic and adverse effects of mu-opioid receptor agonists are largely mediated by G protein signaling, and that many purported G protein-biased agonists may actually be low-intrinsic-efficacy agonists.

Summary: This paper examines the concept of biased versus partial agonism in developing safer opioid analgesics, focusing on the mu opioid receptor. While opioids like morphine are effective for pain, they cause significant adverse effects. Studies suggest that drugs biased away from beta-arrestin signaling may have a reduced side-effect profile, with examples like oliceridine, PZM21, and SR–17018 showing preclinical promise. However, the authors caution that some of these compounds may act as partial agonists, and their therapeutic indices might correlate with efficacy rather than bias factors, suggesting that reduced efficacy could explain 'apparent bias' and lead to analgesia with fewer side effects. The paper advocates for caution in attributing reduced side effects solely to biased agonism for mu-agonist analgesics.

Summary: This perspective reviews recent advances in biased ligands for G protein-coupled receptors (GPCRs), focusing on structure-functional selectivity relationships (SFSRs) and therapeutic potential. It explains that biased ligands, selective for either G-protein-dependent or G-protein-independent pathways (like beta-arrestin recruitment), can offer more precise regulation of GPCR functions, leading to drugs with improved efficacy and reduced side effects. The paper highlights the development of such ligands for various GPCRs, including the mu opioid receptor and angiotensin II receptor type 1, and emphasizes that further understanding of signaling pathways and structural bases will aid future drug design.

Summary: This review explores biased signaling, also known as functional selectivity, as a key concept for developing improved G-protein-coupled receptor (GPCR) drugs with enhanced therapeutic effectiveness and reduced side effects. It highlights opioid analgesics as a prime example, where biased agonists are being investigated to separate potent pain relief from serious side effects by modulating the balance between G-protein and β-arrestin signaling. The paper discusses recent advancements in evaluating individual signaling pathways and provides an overview of biased signaling in opioid receptors, particularly the μ-opioid receptor (MOR), along with methods for assessing signaling bias and future directions for rational drug development.

Summary: This review provides a comprehensive overview of biased ligands and their calculated bias factors specifically for the opioid family of receptors, highlighting the impact of G protein-biased ligands on drug design and medicine.

Summary: This review discusses the development of biased agonists for the mu-opioid receptor (μ-OR), a key GPCR for pain management, aiming to overcome the adverse effects associated with traditional opioid analgesics like morphine. It highlights that selective activation of the Gi signaling pathway over β-arrestin signaling can lead to reduced gastrointestinal dysfunction and respiratory suppression. The paper explores strategies for developing these biased μ-OR agonists and suggests areas for future improvement, with a focus on the structural basis of ligand-receptor interactions.

Summary: This review focuses on opioid signaling and the design of analgesics, highlighting the clinical use of opioids for pain management and their associated side effects, including the ongoing opioid epidemic. It discusses how research into opioid receptors, a class of GPCRs, and the phenomenon of biased agonism are crucial for developing potent analgesics with diminished side effects. The paper explains that opioid receptors activate G-protein and/or beta-arrestin2 pathways, and the development of safer analgesics for mu and kappa opioid receptor subtypes involves strategies like not recruiting beta-arrestin2 (biased agonism) or having low efficacy (partial agonism). The authors intend to explore ligands with bias profiles, receptor signaling aspects, and the structural basis for bias and partial agonism.

Summary: This review examines the therapeutic potential of signaling bias in opioid analgesics for pain management, acknowledging their efficacy but also their severe side effects. It discusses how ligand-specific modulation of receptor functions, particularly the bias towards G protein or β-arrestin pathways, has been explored to improve opioid therapy. However, the paper highlights recent challenges to the hypothesis linking β-arrestin to side effects, suggesting that newly developed biased drugs may not offer the expected superior side effect profiles. It also notes the complexity introduced by the time- and cell-dependent nature of biased agonism at opioid receptors, and explores how signaling kinetics and cellular context influence bias for therapeutic exploitation.

Summary: This review article explores the role of internalized G protein-coupled receptors (GPCRs) in pain management, moving beyond classical cell-surface signaling. It highlights that following activation, GPCRs can be internalized via mechanisms involving β-arrestin and clathrin-mediated endocytosis, leading to a distinct 'second wave' of signaling from intracellular compartments like endosomes and the Golgi. Understanding these spatiotemporally distinct intracellular signaling events is crucial for comprehending pain mechanisms, the efficacy of current analgesics, and the development of new analgesic strategies, particularly through "location-biased" ligands that target intracellular GPCR populations.

Summary: This paper reviews the role of the angiotensin II type 1 (AT1) receptor in cerebrovascular diseases, noting that while current treatments like ARBs are used for cardiovascular diseases, they show limited efficacy in clinical stroke studies. It highlights the emerging therapeutic strategies based on biased AT1 agonists that selectively activate the β-arrestin pathway over the Gq pathway, suggesting these alternative signaling pathways offer new therapeutic avenues for cerebrovascular diseases.

Summary: This review explores the role of β-arrestin as a therapeutic target in heart failure, a condition exacerbated by maladaptive sympathetic hyperactivity. It highlights how β-arrestin modulates signaling from β-adrenergic and angiotensin II receptors, which are targeted by current heart failure therapies. The paper discusses the potential of developing GPCR agonists biased towards β-arrestin activation to limit deleterious signaling while promoting cardioprotective cascades, thereby preserving cardiac structure and function. It also examines the functional diversity of cardiac β-arrestin isotypes and the challenges in translating these findings into clinical applications.

Summary: This paper explores the emerging therapeutic strategies for cardiovascular disease by focusing on the downstream mediators of G protein-coupled receptor (GPCR) activity. It highlights how targeted approaches can bias receptor activation towards specific signaling pathways, such as G proteins versus GPCR kinases (GRKs) and β-arrestins, leading to divergent functional outcomes. The research also discusses the noncanonical roles of GRKs and β-arrestins in modulating GPCR signaling and identifies novel complexes with significant impacts on cardiac function. By identifying new GPCR targets and ligands with beneficial cardiovascular effects, the paper emphasizes the potential for developing therapies that selectively activate beneficial pathways while inhibiting detrimental ones.

Summary: This review focuses on biased opioid receptor agonists, which aim to enhance analgesic efficacy while mitigating side effects by preferentially activating G protein signaling over β-arrestin signaling. It explores the hypothesis that G protein pathways mediate pain relief, while β-arrestin pathways contribute to adverse effects, noting that recent research challenges earlier findings on β-arrestin's role in side effects. The paper delves into the contradictory roles of β-arrestin signaling in opioid-related adverse reactions and includes a comparative analysis of classic G protein-biased agonists (TRV130, PZM21) against the traditional agonist morphine, with the goal of informing the development of safer and more effective analgesic drugs.

Summary: This review discusses biased agonism as a novel approach to developing improved opioid analgesics, aiming to overcome the limitations of traditional opioid drugs like morphine, which are effective for severe pain but cause significant unwanted side effects. It highlights how biased ligands can differentially activate downstream signaling pathways of opioid receptors, offering a strategy to separate desired analgesic effects from adverse reactions. The paper summarizes current knowledge on peptide and nonpeptide opioid ligands, illustrating the evolution of opioid pharmacology through this selective activation concept.

Summary: This paper reviews the concept of ligand bias as a strategy to improve drug therapeutic profiles, particularly for G protein-coupled receptors (GPCRs) involved in analgesia. It discusses how separating analgesic effects from adverse effects by targeting different cellular signaling pathways (e.g., G protein vs. beta-arrestin) could be advantageous, noting that while this has been explored for the mu-opioid receptor, its significant benefit for pain treatment remains uncertain. However, the development of biased ligands at other CNS GPCRs shows promise for future novel analgesic drugs.

Summary: This paper explores the potential of quantitative systems pharmacology (QSP) models to advance the development of improved analgesics through biased agonism at opioid receptors. It highlights that while G protein signaling is linked to antinociception and arrestin pathways to adverse effects, the reality of opioid receptor pharmacology is more complex than a simple G protein vs. arrestin dichotomy. The abstract suggests that QSP models, combined with multidimensional assays and computational analysis, are crucial for dissecting this complexity and overcoming current limitations in translating G protein-biased opioid agonists into effective therapeutics for chronic pain.

Summary: This review discusses new pharmacological strategies for analgesic drug development, focusing on biased µ-opioid receptor (MOR) agonists as a potential treatment for chronic pain. It highlights that while opioids are effective for moderate to severe pain, their use is limited by side effects like tolerance and hyperalgesia. Biased agonists, which modulate different downstream pathways to discriminate between analgesic and adverse effects, are presented as a promising strategy. The paper reviews the pharmacological outcomes of opioid biased ligands, integrating cellular results with clinical trial data, with a particular emphasis on the therapeutic relevance of biased MOR agonists, acknowledging some criticisms but positioning the strategy as a useful step towards safer opioid analgesics.

Summary: This review examines the concept of functional selectivity or biased agonism in the context of β-adrenergic and angiotensin II type 1A receptors, which are important therapeutic targets for cardiovascular diseases like hypertension and heart failure. It highlights that while antagonists for these receptors have shown significant benefits, these benefits might be partially explained by functional selectivity, where a single ligand-receptor interaction can differentially modify multiple signaling pathways. The paper focuses on signaling via both G protein-dependent and G protein-independent mechanisms, particularly the role of β-arrestin, and discusses how ligand/receptor modifications can influence biased agonism, with implications for developing next-generation cardiovascular drugs.

Summary: This review focuses on beta-arrestin-dependent signaling mediated by cardiovascular GPCRs, such as beta-adrenergic and angiotensin II type 1 receptors. It highlights how beta-arrestin binding, following GRK phosphorylation, uncouples receptors from G proteins and targets them for internalization, while also acting as scaffolds for independent signaling waves. The paper discusses the increasing evidence implicating beta-arrestin signaling in cardiovascular physiology and pathology, presenting opportunities for therapeutic intervention in cardiovascular disorders through the use of 'biased' ligands that selectively activate or inhibit specific beta-arrestin-mediated pathways, thereby revising classical pharmacological concepts.

Summary: This review discusses G Protein-Coupled Receptors (GPCRs) as major drug targets, highlighting the classical understanding of their signaling via G proteins and the emerging role of β-arrestins in regulating GPCR-associated intracellular signaling pathways. It explains biased agonism as the ability of GPCR ligands to preferentially activate either the G protein or β-arrestin pathway, with each pathway potentially mediating distinct therapeutic effects or side effects. The paper focuses on summarizing current research on biased agonists for GPCRs, with a specific emphasis on their potential as a therapeutic strategy for cardiovascular diseases.

Summary: This review summarizes recent studies on biased G protein-coupled receptor (GPCR) signaling, highlighting the discovery of novel roles for β-arrestins as signal transducers in G protein-independent pathways. This has led to the concept of biased agonism, where ligands preferentially activate specific downstream signaling pathways (G protein or β-arrestin mediated). The paper discusses how this approach offers potential for developing highly selective, next-generation drugs targeting therapeutically relevant GPCR signaling pathways to modulate pathophysiological processes.

Summary: This paper reviews biased agonism at beta-adrenergic receptors (βARs), which are involved in cardiovascular and metabolic functions, and are targets for treating hypertension, heart failure, and asthma. It highlights that current βAR ligands can have suboptimal efficacy and side effects, proposing biased agonists that selectively activate specific signaling pathways (Gs or β-arrestin) as a strategy to improve treatments. The review discusses compounds identified to date that show such biased signaling through βARs and explores the mechanistic insights that could lead to more selective compounds with increased therapeutic utility.

Summary: This review focuses on G protein-coupled receptors (GPCRs) as therapeutic targets for chronic pain. It explains that GPCRs are crucial for pain sensation, acting on neurons at peripheral, spinal cord, and brain levels to regulate nociceptive activities. The abstract highlights that GPCRs are significantly altered in chronic pain states, suggesting their potential as novel targets for therapeutic intervention in this complex condition.

Summary: This review explores biased agonism of G protein-coupled receptors (GPCRs) as a novel therapeutic strategy for osteoarthritis (OA), a degenerative joint disorder characterized by chronic pain and inflammation. It highlights how biased ligands, which selectively activate specific GPCR signaling pathways (e.g., G protein vs. β-arrestin), can potentially optimize therapeutic efficacy and reduce side effects compared to traditional treatments. The paper examines biased signaling in various OA-associated GPCRs, including cannabinoid, chemokine, protease-activated, adenosine, melanocortin, bradykinin, prostaglandin E2, and calcium-sensing receptors, and discusses ligands in clinical trials and natural products from Traditional Chinese Medicine as potential biased agonists for developing targeted OA therapies.

Summary: This review explores the potential of biased ligands, which selectively engage specific G protein or β-arrestin pathways, as a strategy for developing more effective and better-tolerated drugs, particularly at endothelin receptors. It discusses re-analyzing existing data to identify pathway bias in endogenous peptides and current ligands, and introduces cell-penetrating peptides like IC2B that modify receptor signaling and have shown efficacy in pulmonary arterial hypertension. The abstract also highlights the importance of understanding molecular pathways in disease, such as ETA signaling in ovarian cancer, to guide the development of biased agonists or antagonists.

Summary: This review serves as a foundational introduction to biased agonism in G protein-coupled receptor (GPCR) pharmacology, aiming to clarify the concept for clinicians and pharmacists. It explains classical pharmacology and GPCR signal transduction, with a particular focus on biased agonists of beta-adrenergic receptors, such as carvedilol, which are widely prescribed. The paper highlights the clinical relevance and the need for a deeper understanding of biased agonism for developing novel therapeutic strategies, mentioning its relevance to receptors like the angiotensin type 1 receptor and parathyroid hormone receptor in subsequent reviews.

Summary: This paper reviews evidence that GPCRs and RTKs mediate chronic pain through sustained signals generated in intracellular compartments. It suggests that targeting these intracellular signals, rather than surface receptors, may offer more effective and long-lasting pain relief, and highlights the potential of identifying coreceptors and molecular scaffolds as new therapeutic targets for chronic pain.