Pharmacology & Therapeutics最新文献_第4页

Biased agonism in peptide-GPCRs: A structural perspective.

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2025-01-29 DOI: 10.1016/j.pharmthera.2025.108806

Tharindunee Jayakody, Dinath Kavishka Budagoda, Krishan Mendis, Withanage Dhanuka Dilshan, Duvindu Bethmage, Rashmi Dissasekara, Gavin Stewart Dawe

引用次数: 0

Bridging the gap: The endocannabinoid system as a functional fulcrum for benzodiazepines in a novel frontier of anxiety pharmacotherapy 缩小差距：内源性大麻素系统作为苯二氮卓类药物的功能支点，开辟了焦虑症药物治疗的新领域。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2025-01-23 DOI: 10.1016/j.pharmthera.2025.108799

Sina Pakkhesal , Mohammad Shakouri , Reza Mosaddeghi-Heris , Sepideh Kiani Nasab , Negin Salehi , AmirMohammad Sharafi , Ali Ahmadalipour

{"title":"Bridging the gap: The endocannabinoid system as a functional fulcrum for benzodiazepines in a novel frontier of anxiety pharmacotherapy","authors":"Sina Pakkhesal , Mohammad Shakouri , Reza Mosaddeghi-Heris , Sepideh Kiani Nasab , Negin Salehi , AmirMohammad Sharafi , Ali Ahmadalipour","doi":"10.1016/j.pharmthera.2025.108799","DOIUrl":"10.1016/j.pharmthera.2025.108799","url":null,"abstract":"<div><div>While benzodiazepines have been a mainstay of the pharmacotherapy of anxiety disorders, their short-term efficacy and risk of abuse have driven the exploration of alternative treatment approaches. The endocannabinoid (eCB) system has emerged as a key modulator of anxiety-related processes, with evidence suggesting dynamic interactions between the eCB system and the GABAergic system, the primary target of benzodiazepines. According to the existing literature, the activation of the cannabinoid receptors has been shown to exert anxiolytic effects, while their blockade or genetic deletion results in heightened anxiety-like responses. Moreover, studies have provided evidence of interactions between the eCB system and benzodiazepines in anxiety modulation. For instance, the attenuation of benzodiazepine-induced anxiolysis by cannabinoid receptor antagonism or genetic variations in the eCB system components in animal studies, have been associated with variations in benzodiazepine response and susceptibility to anxiety disorders. The combined use of cannabinoid-based medications, such as cannabinoid receptor agonists and benzodiazepine co-administration, has shown promise in augmenting anxiolytic effects and reducing benzodiazepine dosage requirements. This article aims to comprehensively review and discuss the current evidence on the involvement of the eCB system as a key modulator of benzodiazepine-related anxiolytic effects, and further, the possible mechanisms by which the region-specific eCB system-GABAergic connectivity modulates the neuro-endocrine/behavioral stress response, providing an inclusive understanding of the complex interplay between the eCB system and benzodiazepines in the context of anxiety regulation, to inform future research and clinical practice.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"267 ","pages":"Article 108799"},"PeriodicalIF":12.0,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143035674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Attributes novel drug candidate: Constitutive GPCR signal bias mediated by purinergic receptors

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2025-01-23 DOI: 10.1016/j.pharmthera.2025.108802

Li Yin , Kexin Ni , Tianqi Mao , Sheng Tian , Chunxiao Liu , Jiayao Chen , Mengze Zhou , Huanqiu Li , Qinghua Hu

{"title":"Attributes novel drug candidate: Constitutive GPCR signal bias mediated by purinergic receptors","authors":"Li Yin , Kexin Ni , Tianqi Mao , Sheng Tian , Chunxiao Liu , Jiayao Chen , Mengze Zhou , Huanqiu Li , Qinghua Hu","doi":"10.1016/j.pharmthera.2025.108802","DOIUrl":"10.1016/j.pharmthera.2025.108802","url":null,"abstract":"<div><div>G protein-coupled receptors (GPCRs) can transmit signals via G protein-dependent or independent pathways due to the conformational changes of receptors and ligands, which is called biased signaling. This concept posits that ligands can selectively activate a specific signaling pathway after receptor activation, facilitating downstream signaling along a preferred pathway. Biased agonism enables the development of ligands that prioritize therapeutic signaling pathways while mitigating on-target undesired effects. As a class of GPCRs located on the surface of cell membranes, the discovery and clinical implementation of adenosine and P2Y receptors purinergic signaling modulators have progressed dramatically. However, many preclinical drug candidates targeting purinergic receptors have failed in clinical trials due to limited efficacy and/or severe on-target undesired effects. To overcome the key barriers typically encountered when transitioning ligands into the clinic, the renewed impetus has focused on the modulation of purinergic receptor function by exogenous agonists/antagonists and allosteric modulators to exploit biased agonism. This article provides a brief overview of the research progress on the mechanism of purinergic biased signal transduction from the conformational changes of purinergic GPCRs and biased ligands primarily, and highlights therapeutically relevant biased agonism at purinergic receptors.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"267 ","pages":"Article 108802"},"PeriodicalIF":12.0,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143035672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Semaphorin 3s signaling in the central nervous system: Mechanisms and therapeutic implication for brain diseases

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2025-01-23 DOI: 10.1016/j.pharmthera.2025.108800

Ya-Ping Lu , Yi-Ling Luo , Zhou-Yue Wu , Chao Han , Yin-Zhi Jin , Jun-Ming Han , Shu-Yang Chen , Fei Teng , Feng Han , Xiu-Xiu Liu , Ying-Mei Lu

引用次数: 0

Roles of NLRC4 inflammasome in neurological disorders: Mechanisms, implications, and therapeutic potential NLRC4 炎性体在神经系统疾病中的作用：机制、影响和治疗潜力

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2025-01-22 DOI: 10.1016/j.pharmthera.2025.108803

Wen Zhang , Li Zhang , Shuo Fu , Rong Yan , Xue Zhang , Junke Song , Yang Lu

{"title":"Roles of NLRC4 inflammasome in neurological disorders: Mechanisms, implications, and therapeutic potential","authors":"Wen Zhang , Li Zhang , Shuo Fu , Rong Yan , Xue Zhang , Junke Song , Yang Lu","doi":"10.1016/j.pharmthera.2025.108803","DOIUrl":"10.1016/j.pharmthera.2025.108803","url":null,"abstract":"<div><div>The nucleotide-binding oligomerization domain-like receptor family caspase recruitment domain containing 4 (NLRC4) inflammasome, a vital component of the innate immune system, is known for defending against bacterial infections. However, recent insights have revealed its significant impact on neurological disorders. This comprehensive review discussed the mechanisms underlying the activation and regulation of the NLRC4 inflammasome, highlighting the complexity of its response to cellular stress and damage signals. The biological functions of NLRC4 were explored, particularly its influence on cytokine production and the induction of pyroptosis, a form of inflammatory cell death. This review further emphasized the role of the NLRC4 inflammasome in brain injuries and neurodegenerative disorders. In the realm of brain injuries such as stroke and traumatic brain injury, as well as in neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis, the NLRC4 inflammasome played a pivotal role in modulating neuroinflammatory responses, which was crucial for understanding the progression and potential therapeutic targeting of these conditions. The emerging role of NLRC4 in psychiatric disorders and its potential impact on glioma progression were also examined. Additionally, this review presented a thorough summary of the latest research on inhibitors that impeded the assembly and activation of the NLRC4 inflammasome, pointing to new therapeutic possibilities in neurological disorders. In conclusion, by integrating current knowledge on the activation and regulation of NLRC4 with its biological functions and clinical implications, this article underscored the importance of NLRC4 inflammasome in neurological pathologies, which opened new possibilities for the treatment of challenging neurological conditions.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"267 ","pages":"Article 108803"},"PeriodicalIF":12.0,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143035801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cannabinoid receptor 1 ligands: Biased signaling mechanisms driving functionally selective drug discovery 大麻素受体1配体：偏倚信号机制驱动功能选择性药物发现。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2025-01-17 DOI: 10.1016/j.pharmthera.2025.108795

Lei Tian , Taotao Qiang , Sundian Liu , Boxin Zhang , Yunfei Zhang , Bingxing Zhang , Jinrong Hu , Jiayun Zhang , Qi Lu , Changhua Ke , Juan Xia , Chengyuan Liang

{"title":"Cannabinoid receptor 1 ligands: Biased signaling mechanisms driving functionally selective drug discovery","authors":"Lei Tian , Taotao Qiang , Sundian Liu , Boxin Zhang , Yunfei Zhang , Bingxing Zhang , Jinrong Hu , Jiayun Zhang , Qi Lu , Changhua Ke , Juan Xia , Chengyuan Liang","doi":"10.1016/j.pharmthera.2025.108795","DOIUrl":"10.1016/j.pharmthera.2025.108795","url":null,"abstract":"<div><div>G protein-coupled receptors (GPCRs) adopt conformational states that activate or inhibit distinct signaling pathways, including those mediated by G proteins or β-arrestins. Biased signaling through GPCRs may offer a promising strategy to enhance therapeutic efficacy while reducing adverse effects. Cannabinoid receptor 1 (CB1), a key GPCR in the endocannabinoid system, presents therapeutic potential for conditions such as pain, anxiety, cognitive impairment, psychiatric disorders, and metabolic diseases. This review examines the structural conformations of CB1 coupling to different signaling pathways and explores the mechanisms underlying biased signaling, which are critical for the design of functionally selective ligands. We discuss the structure-function relationships of endogenous cannabinoids (eCBs), phytocannabinoids, and synthetic cannabinoid ligands with biased properties. Challenges such as the complexity of ligand bias screening, the limited availability of distinctly biased ligands, and the variability in receptor signaling profiles <em>in vivo</em> have hindered clinical progress. Although the therapeutic potential of biased ligands in various clinical conditions remains in its infancy, retrospective identification of such molecules provides a strong foundation for further development. Recent advances in CB1 crystallography, particularly insights into its conformations with G proteins and β-arrestins, now offer a framework for structure-based drug design. While there is still a long way to go before biased CB1 ligands can be widely used in clinical practice, ongoing multidisciplinary research shows promise for achieving functional selectivity in targeting specific pathways. These progress could lead to the development of safer and more effective cannabinoid-based therapies in the future.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"267 ","pages":"Article 108795"},"PeriodicalIF":12.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142997869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Conformationally adaptive therapeutic peptides for diseases caused by intrinsically disordered proteins (IDPs). New paradigm for drug discovery: Target the target, not the arrow 构象适应性治疗肽对内在无序蛋白（IDPs）引起的疾病。药物发现的新范例：瞄准目标，而不是箭头。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2025-01-17 DOI: 10.1016/j.pharmthera.2025.108797

Jacques Fantini , Fodil Azzaz , Coralie Di Scala , Anaïs Aulas , Henri Chahinian , Nouara Yahi

{"title":"Conformationally adaptive therapeutic peptides for diseases caused by intrinsically disordered proteins (IDPs). New paradigm for drug discovery: Target the target, not the arrow","authors":"Jacques Fantini , Fodil Azzaz , Coralie Di Scala , Anaïs Aulas , Henri Chahinian , Nouara Yahi","doi":"10.1016/j.pharmthera.2025.108797","DOIUrl":"10.1016/j.pharmthera.2025.108797","url":null,"abstract":"<div><div>The traditional model of protein structure determined by the amino acid sequence is today seriously challenged by the fact that approximately half of the human proteome is made up of proteins that do not have a stable 3D structure, either partially or in totality. These proteins, called intrinsically disordered proteins (IDPs), are involved in numerous physiological functions and are associated with severe pathologies, e.g. Alzheimer, Parkinson, Creutzfeldt-Jakob, amyotrophic lateral sclerosis (ALS), and type 2 diabetes. Targeting these proteins is challenging for two reasons: i) we need to preserve their physiological functions, and ii) drug design by molecular docking is not possible due to the lack of reliable starting conditions. Faced with this challenge, the solutions proposed by artificial intelligence (AI) such as AlphaFold are clearly unsuitable. Instead, we suggest an innovative approach consisting of mimicking, in short synthetic peptides, the conformational flexibility of IDPs. These peptides, which we call adaptive peptides, are derived from the domains of IDPs that become structured after interacting with a ligand. Adaptive peptides are designed with the aim of selectively antagonizing the harmful effects of IDPs, without targeting them directly but through selected ligands, without affecting their physiological properties. This “target the target, not the arrow” strategy is promised to open a new route to drug discovery for currently undruggable proteins.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"267 ","pages":"Article 108797"},"PeriodicalIF":12.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142997874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Unfolded protein responses: Dynamic machinery in wound healing 未折叠蛋白反应：伤口愈合的动态机制。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2025-01-17 DOI: 10.1016/j.pharmthera.2025.108798

Morgan Minjares , Pattaraporn Thepsuwan , Kezhong Zhang , Jie-Mei Wang

{"title":"Unfolded protein responses: Dynamic machinery in wound healing","authors":"Morgan Minjares , Pattaraporn Thepsuwan , Kezhong Zhang , Jie-Mei Wang","doi":"10.1016/j.pharmthera.2025.108798","DOIUrl":"10.1016/j.pharmthera.2025.108798","url":null,"abstract":"<div><div>Skin wound healing is a dynamic process consisting of multiple cellular and molecular events that must be tightly coordinated to repair the injured tissue efficiently. The healing pace is decided by the type of injuries, the depth and size of the wounds, and whether wound infections occur. However, aging, comorbidities, genetic factors, hormones, and nutrition also impact healing outcomes. During wound healing, cells undergo robust processes of synthesizing new proteins and degrading multifunctional proteins. This imposes an increasing burden on the endoplasmic reticulum (ER), causing ER stress. Unfolded protein response (UPR) represents a collection of highly conserved stress signaling pathways originated from the ER to maintain protein homeostasis and modulate cell physiology. UPR is known to be beneficial for tissue healing. However, when excessive ER stress exceeds ER's folding potential, UPR pathways trigger cell apoptosis, interrupting tissue regeneration. Understanding how UPR pathways modulate the skin's response to injuries is critical for new interventions toward the control of acute and chronic wounds. Herein, in this review, we focus on the participation of the canonical and noncanonical UPR pathways during different stages of wound healing, summarize the available evidence demonstrating UPR's unique position in balancing homeostasis and pathophysiology of healing tissues, and highlight the understudied areas where therapeutic opportunities may arise.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"267 ","pages":"Article 108798"},"PeriodicalIF":12.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142997892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

G protein-coupled purinergic P2Y receptors in infectious diseases G蛋白偶联嘌呤能P2Y受体在传染病中的作用。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2025-01-13 DOI: 10.1016/j.pharmthera.2025.108796

Letícia de Almeida Carvalho , Vinícius Santos Alves , Robson Coutinho-Silva , Luiz Eduardo Baggio Savio

{"title":"G protein-coupled purinergic P2Y receptors in infectious diseases","authors":"Letícia de Almeida Carvalho , Vinícius Santos Alves , Robson Coutinho-Silva , Luiz Eduardo Baggio Savio","doi":"10.1016/j.pharmthera.2025.108796","DOIUrl":"10.1016/j.pharmthera.2025.108796","url":null,"abstract":"<div><div>The purinergic P2Y receptors comprise eight G-coupled receptor (GPCR) subtypes already identified (P2Y<sub>1</sub>, P2Y<sub>2</sub>, P2Y<sub>4</sub>, P2Y<sub>6</sub>, P2Y<sub>11</sub>, P2Y<sub>12</sub><sub>–</sub><sub>14</sub>). P2Y receptor physiological agonists are extracellular purine and pyrimidine nucleotides such as ATP (Adenosine triphosphate), ADP (Adenosine diphosphate), UTP (Uridine triphosphate), UDP (Uridine diphosphate), and UDP-glucose. These receptors are expressed in almost all cells. P2Y receptors are found in immune cells, such as macrophages, neutrophils, mast cells, dendritic cells, and lymphocytes. P2Y receptors play essential roles in inflammation and are involved in several cell processes, including efferocytosis, phagocytosis, chemotaxis, degranulation, killing pathogens, cytokine production, and platelet aggregation. These processes underpin immune responses against pathogens. Therefore, here we discuss P2Y receptor pharmacology and mechanisms triggered by the activation of these receptors in virus, bacteria, and parasite infections. In addition, we highlight the therapeutical potential of P2Y receptors for developing new pharmacological strategies to modulate inflammation and disease outcomes in pathogen infections.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"267 ","pages":"Article 108796"},"PeriodicalIF":12.0,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142997887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Healing action of Interleukin-4 (IL-4) in acute and chronic inflammatory conditions: Mechanisms and therapeutic strategies 白介素-4 （IL-4）在急慢性炎症中的愈合作用：机制和治疗策略。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2025-01-01 DOI: 10.1016/j.pharmthera.2024.108760

Kai Pan , Qiong Li , Zhikun Guo , Zongjin Li

{"title":"Healing action of Interleukin-4 (IL-4) in acute and chronic inflammatory conditions: Mechanisms and therapeutic strategies","authors":"Kai Pan , Qiong Li , Zhikun Guo , Zongjin Li","doi":"10.1016/j.pharmthera.2024.108760","DOIUrl":"10.1016/j.pharmthera.2024.108760","url":null,"abstract":"<div><div>Interleukin-4 (IL-4), which is traditionally associated with inflammation, has emerged as a key player in tissue regeneration. Produced primarily by T-helper 2 (Th2) and other immune cells, IL-4 activates endogenous lymphocytes and promotes M2 macrophage polarization, both of which are crucial for tissue repair. Moreover, IL-4 stimulates the proliferation and differentiation of various cell types, contributing to efficient tissue regeneration, and shows promise for promoting tissue regeneration after injury. This review explores the multifaceted roles of IL-4 in tissue repair, summarizing its mechanisms and potential for clinical application. This review delves into the multifaceted functions of IL-4, including its immunomodulatory effects, its involvement in tissue regeneration, and its potential therapeutic applications. We discuss the mechanisms underlying IL-4-induced M2 macrophage polarization, a crucial process for tissue repair. Additionally, we explore innovative strategies for delivering IL-4, including gene therapy, protein-based therapies, and cell-based therapies. By leveraging the regenerative properties of IL-4, we can potentially develop novel therapies for various diseases, including chronic inflammatory disorders, autoimmune diseases, and organ injuries. While early research has shown promise for the application of IL-4 in regenerative medicine, further studies are needed to fully elucidate its therapeutic potential and optimize its use.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"265 ","pages":"Article 108760"},"PeriodicalIF":12.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0