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 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.

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 Gi/o/z protein pathway and the β-arrestin1/2 pathway. Recent research has indicated that G protein-biased agonists, which preferentially activate the Gi/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 15years 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.

GPCRs are known for their versatile signaling roles at the plasma membrane; however, recent studies have revealed that these receptors also function within various intracellular compartments, such as endosomes, the Golgi apparatus, and the endoplasmic reticulum. This spatially distinct signaling, termed location bias, allows GPCRs to initiate unique signaling cascades and influence cellular processes-including cAMP production, calcium mobilization, and protein phosphorylation-in a compartment-specific manner. By mapping the impact of GPCR signaling from these subcellular locations, this chapter emphasizes the mechanisms underlying signaling from intracellular receptor pools in diversifying receptor functionality. Such mechanistic insights into location-biased signaling open up novel therapeutic strategies aimed at targeting GPCRs within specific organelles, promising new levels of precision in therapeutic modulation and potential improvements in treatment efficacy and specificity.

Selectivity of a drug for a desired response as compared to undesirable responses (side effect) is a key goal of drug development. Early concepts to achieve such selectivity were based on selectivity for a molecular target as compared to others, pharmacokinetic factors to achieve high concentrations in the target tissue as compared to low concentrations in others, differential efficacy in the target vs. others tissues, and leveraging the concept of cell type and tissue differences in expression levels of receptors and their related signaling molecules, which can be further complicated by alterations of such ratios in disease. Biased agonism occurs when one response is activated preferentially over another after accounting for theabove otherfactors. Thus, assessment of ligand bias is not always easy. β-Adrenoceptors have played a relevant role in our understanding of the phenomenon of biased agonism. Several clinically used β-adrenoceptor ligands were proposed to exhibit biased agonism, but the findings often are inconclusive, at least partly based on the overall complexity of assessment of biased signaling. These complexities also make it challenging to determine the desired biased profile of a ligand at the start of a drug research and development project, particularly for innovative applications. Thus, biased agonism has potential to contribute to functional target selectivity, but its prospective use remains challenging.

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.

Perivascular adipose tissue (PVAT) is a metabolically active, endocrine organ that plays a crucial role in regulating blood vessel tone, endothelial function, vascular smooth muscle cell growth, and proliferation and contributes significantly to the onset and progression of cardiovascular diseases. In a healthy state, PVAT displays anticontractile, anti-inflammatory, and antioxidative properties, which are critical for maintaining vascular homeostasis. However, under certain pathophysiological conditions, PVAT exerts pro-contractile effects by decreasing the production of anticontractile and/or increasing that of pro-contractile factors. In this context, recent studies have identified hydrogen sulfide (H2S) as a key vascular anti-contractile factor released from PVAT. The enzymes responsible for H2S biosynthesis are differentially expressed in PVAT, depending on the vascular bed and species, and their function can be altered by metabolic and cardiovascular diseases. These alterations can influence H2S signalling, further contributing to vascular dysfunction. PVAT-derived H2S may have particular importance in obesity-related vascular disease, hypertension, and diabetes as it has direct paracrine effects on the vasculature. Understanding the role of PVAT-derived H2S in both healthy and diseased states may provide new insights into preventing vascular dysfunction associated with PVAT changes. The dissection of the specific contributions of each enzyme involved in PVAT-derived H2S biosynthesis could be relevant to fully understanding the complex role of H2S in vascular health vs vascular disease. Further research into modulating PVAT-derived H2S provides an exciting avenue to explore novel pharmacological targets against vascular disease pathogenesis.

The chapter provides a brief overview on current methodologies for the assembly of complex oligosaccharides by chemical synthesis. Following an introductory section describing the major factors and variables involved in glycosylation reactions, select examples for advanced approaches towards mammalian and bacterial glycans are discussed illustrating recent progress in the field of glycochemistry.