Handbook of experimental pharmacology最新文献

Atrial fibrillation is the most common cardiac arrhythmia in adults, affecting approximately 59.7 million people worldwide as of 2019-a 111% increase since 1990. Over the past 20 years, the prevalence of AF has risen by 33%, and it is projected to increase by more than 60% by 2050. Age plays a critical role in the factors that contribute to AF. Its prevalence is low (0.1%) in adults under 55 years old but rises to 5.9% in individuals aged 65 and older and 9.0% in those aged 80 and older. In this chapter, we provide a brief history of vitamin K antagonists and direct oral anticoagulants, both of which play a paramount role in atrial fibrillation. We also review the main differences between these two classes of anticoagulants. Furthermore, we aim to address the most common issues associated with DOACs use, particularly concerning patients with renal failure, obesity, and elderly or frail individuals. Lastly, we will discuss some remarks on randomized controlled trials and their limitations. The pivotal role of anticoagulation clinics is also highlighted here, underscoring the need for regular follow-up of both VKAs and DOACs.

Platelets are a crucial component in the maintenance of normal haemostasis. In response to vascular damage, activated platelets adhere to the damaged endothelium leading to both aggregation and coagulation. Under healthy conditions, these processes prevent excessive vascular haemorrhage and promote vascular repair and regeneration. However, in cardiovascular diseases, hyperactive platelet activation leads to acute coronary syndrome characterised by occlusive thrombus formation, myocardial infarction and stroke. Targeted platelet therapy has been used extensively in the inhibition of inappropriate platelet activation for the treatment of cardiovascular diseases including cyclooxygenase inhibitors, purinergic antagonists, thrombin inhibitors, PAR receptor antagonists, and phosphodiesterase inhibitors. In this review, we discuss the current clinical portfolio of antiplatelet therapies whilst also discussing promising new antiplatelet targets for the treatment of cardiovascular disorders.

G protein-coupled receptors (GPCRs) constitute the largest superfamily of membrane receptors in humans and serve as crucial targets for drug development. These receptors engage multiple downstream signaling pathways, including various G-proteins and arrestins, each of which can elicit distinct physiological and pathological responses. Understanding the mechanisms of biased signaling among these pathways is vital for designing more effective drugs with reduced side effects. In this chapter, we summarize the current understanding of how GPCRs selectively couple to different signaling proteins. We delve into the structural insights derived from recent studies, which reveal how ligands can stabilize specific receptor conformations, thereby favoring particular signaling pathways over others. Furthermore, we highlight various biased ligands and their mechanisms of action, emphasizing their therapeutic potential. These findings provide a critical structural foundation for future drug discovery and optimization efforts, paving the way for more targeted and safer pharmacological interventions. Through a deeper comprehension of biased signaling mechanisms, we aim to enhance the efficacy and safety profiles of new therapeutic agents.

G protein-coupled receptors (GPCRs) are highly dynamic membrane receptors with numerous subtypes and complex signal transduction pathways. Precise regulation of GPCR signaling is closely related to disease treatment but presents significant challenges with classical orthosteric ligands. Allosteric modulators, a class of emerging drug candidates, can selectively bind to the allosteric sites located outside the conserved orthosteric pocket. In particular, biased allosteric modulators (BAMs) can stabilize specific conformations of GPCRs to harness signal transduction with high selectivity and specificity, offering a novel approach to modulate GPCR pharmacology and develop safer therapeutic agents. In recent years, significant progress has been made in the study of GPCR allosteric modulation due to advancements in structural biology. However, knowledge about GPCR-biased allostery is still in its infancy. In this chapter, we present the most recent breakthroughs in the discovery of BAM binding site in GPCRs and provide structural insights into biased allostery of GPCR signaling.

G protein-coupled receptors (GPCRs) are the largest family of transmembrane receptors and the most prominent drug targets. GPCR-biased signaling exerts different functions through distinct downstream signaling pathways of receptor to maintain body homeostasis. Metabolism is the series of biochemical processes that occur within a living organism to maintain life. GPCR-biased signaling and metabolism exhibit bidirectional interplay. On the one hand, metabolites including short-chain fatty acids (SCFAs) and long-chain fatty acids (LCFAs) act as ligands inducing biased GPCRs signaling. On the other hand, activated GPCRs regulate diverse metabolic functions by biased signal sorting (G protein or β-arrestin-mediated). G protein signaling mainly mediates rapid metabolic reaction, and β-arrestin signaling mainly mediates sustained metabolic effects. In clinical drug applications, GPCR-biased drugs can revolutionize metabolic disease therapeutics by enabling pathway-selective drug design to enhance efficacy while reducing side effects. Thus, delving deeper into the relationship between GPCR-biased signaling and metabolism is of great importance in physiology, pathology, and pharmacology. A systematic exploration of biased signaling will enhance insights into GPCRs-metabolism interactions, aiding disease mechanism studies, drug discovery, and clinical treatment strategies.

Upon stimulation by endogenous ligands, G protein-coupled receptors (GPCRs) activate downstream signaling pathways through multiple mechanisms, including G protein subtypes, β-arrestins, and receptor-specific partners. Synthetic ligands may activate only a subset of these pathways, resulting in functional selectivity or signaling bias. Since not all signaling outputs are therapeutically desirable, there is pharmaceutical interest in exploiting biased signaling. Although much effort is focused on designing ligands to induce receptor conformations that result in signal bias, it is also true that cellular systems adapt dynamically in ways that tune receptor signaling, termed system bias. In this chapter, we provide evidence that posttranslational modification of receptor machinery by S-nitrosylation is an important regulator of system bias in GPCR signaling. S-nitrosylation has been reported to affect the function of multiple classes of GPCR signaling pathway components, including receptors, G proteins, G protein-coupled receptor kinases, β-arrestins, and others. Further, untargeted proteomic studies of S-nitrosylated proteins have identified over 60 GPCRs, most heterotrimeric G proteins, and numerous GPCR signaling components, hinting at a class effect and unifying mechanism to bias the functional repertoires of GPCRs in vivo. Thus, protein S-nitrosylation provides prototypic examples for how post-translational regulatory mechanisms bias GPCRs endogenously.

The μ-opioid receptor (μOR) is the primary drug target of opioid analgesics such as morphine and fentanyl. Activation of μORs in the central nervous system inhibits ascending pain signaling to the cortex, thereby producing analgesic effects. However, the clinical use of opioid analgesics is severely limited by adverse side effects, including respiratory depression, constipation, addiction, and the development of tolerance. μOR-mediated signaling involves both the G_i/o/z protein pathway and the β-arrestin1/2 pathway. Recent research has indicated that G protein-biased agonists, which preferentially activate the G_i/o/z pathway over the β-arrestin1/2 pathway, may provide effective analgesia with reduced side effects, thus offering improved therapeutic potential. In this chapter, we review the molecular basis of μOR-biased agonism. By integrating findings from structural and dynamic studies, we summarize the structure-bias relationships of various μOR agonists, aiming to provide valuable insights for the development of next-generation μOR-biased agonists.

Research conducted over the last 15 years indicates that cAMP is generated not just from the plasma membrane but also from intracellular compartments, particularly in endosomes, where receptors are redistributed during the endocytosis process. This review centers on the parathyroid hormone type 1 receptor (PTH₁R) as a model for a peptide hormone GPCRs that generates cAMP from various locations with distinct duration and pharmacological effectiveness. We discuss how structural dynamics simulations aid in designing ligands that induce cAMP location bias, ultimately answering how the spatiotemporal generation of cAMP affects pharmacological responses mediated by the PTH₁R.

G protein-coupled receptors (GPCRs) engage multiple transducers to regulate distinct physiological processes. These transducers include various G proteins subtypes, GPCR kinases (GRKs), and β-arrestins. In addition to promoting receptor desensitization, β-arrestins serve as scaffolds for signaling via non-G protein pathways. Biased signaling enables GPCRs to selectively engage specific transducers, typically through different conformational states of GPCRs. While significant focus has been placed on developing biased ligands that preferentially activate specific G proteins or β-arrestins, the strategy focused on modulating particular G protein subunits (Gα versus βγ) remains underexplored. Recently, members of the KCTD (potassium channel tetramerization domain-containing) family have emerged as critical regulators of GPCR signaling, particularly through their roles in mediating Gβγ degradation or uncoupling Gβγ from downstream effectors. This ability positions the KCTD family as potential targets for selectively modulating Gβγ signaling with minimal impact on Gα-mediated pathways. In this chapter, we introduce the KCTD family, summarize current knowledge of their role in GPCR signaling regulation, and highlight unsolved questions in existing models, along with directions for future research.

G protein-coupled receptor (GPCR) biased signaling has emerged as a transformative paradigm, reshaping both fundamental understanding of receptor biology and pharmacological intervention. Significant advances have been made in deciphering the mechanisms underlying biased signaling and in the development of ligands that selectively engage specific pathways. Here, we outline key future directions in GPCR biased signaling and ligand pharmacology including the biased signaling theories, structural insights, methodological innovations and ligand pharmacology theories. We hope that these perspectives will contribute to pharmacological research, drug R & D, and clinical drug research and promoting safer and more effective GPCR-targeted treatments for human diseases.