Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel, which is considered a highly validated target for pain perception. Repeated activation with agonists to desensitize receptors or use the antagonists can both exert analgesic effects. In this work, two series of novel phenylpiperazine derivatives were designed, synthesized, and evaluated for the in vitro receptor inhibitory activity and in vivo analgesic activity. Among them, L-21 containing sulfonylurea group was identified with potent TRPV1 antagonistic activity and analgesic activity in various pain models. At the same time, L-21 exhibited low risk of hyperthermia side effect. These results indicated that L-21 is a promising candidate for further development of novel TRPV1 antagonist to treat pain.

Chemokine receptor 4 (CXCR4) is a subtype receptor protein of the GPCR family with a seven-transmembrane structure widely distributed in human tissues. CXCR4 is involved in diseases (e.g., HIV-1 infection), cancer proliferation and metastasis, inflammation signaling pathways, and leukemia, making it a promising drug target. Clinical trials on CXCR4 antagonists mainly focused on peptides and antibodies, with a few small molecule compounds, such as AMD11070 (2) and MSX-122 (3), showing promise in cancer treatment. This perspective discusses the structure-activity relationship (SAR) of CXCR4 and its role in diseases, mainly focusing on the SAR of CXCR4 antagonists. It also explores the standard structural features and target interactions of CXCR4 binding in different disease categories. Furthermore, it investigates various modification strategies to propose potential improvements in the effectiveness of CXCR4 drugs.

Analgesia and blood sugar control are considered as two main unmet clinical needs for diabetes related neuropathic pain patients. Transient receptor potential vanilloid type-1 (TRPV1) channel is a highly validated target for pain perception, while no TRPV1 antagonists have been approved due to hyperthermia side effects. Herein, two series of new TRPV1 antagonists with flavonoid skeleton were designed by the structure-based drug design (SBDD) strategy. After comprehensive evaluation, compound CX-3 was identified as a promising TRPV1 antagonist. CX-3 exhibited equivalent TRPV1 antagonistic activity with classical TRPV1 antagonist BCTC in vitro, and exerted better analgesic activity in vivo than that of BCTC in the formalin induced inflammatory pain model without hyperthermia risk. Moreover, CX-3 exhibited robust glucose-lowering effects and showed high selectivity over other ion channels. Overall, these findings identified a first-in-class highly selective TRPV1 antagonist CX-3, which is a promising candidate to target the pathogenesis of diabetes related neuropathic pain.

L-type calcium channels (LTCCs), the largest subfamily of voltage-gated calcium channels (VGCCs), are the main channels for Ca2+ influx during extracellular excitation. LTCCs are widely present in excitable cells, especially cardiac and cardiovascular smooth muscle cells, and participate in various Ca2+-dependent processes. LTCCs have been considered as worthy drug target for cardiovascular, neurological and psychological diseases for decades. Natural products from Traditional Chinese medicine (TCM) have shown the potential as new drugs for the treatment of LTCCs related diseases. In this review, the basic structure, function of LTCCs, and the related human diseases caused by structural or functional abnormalities of LTCCs, and the natural LTCCs antagonist and their potential usages were summarized.

Numerous studies have revealed that the ATP-gated ion channel purinergic 2X7 receptor (P2X7R) plays an important role in tumor progression and the pathogenesis of cancer pain. P2X7R requires activation by extracellular ATP to perform its regulatory role functions. During tumor development or cancer-induced pain, ATP is released from tumor cells or other cells in the tumor microenvironment (such as tumor-associated immune cells), which activates P2X7R, opens ion channels on the cell membrane, affects intracellular molecular metabolism, and regulates the activity of tumor cells. Furthermore, peripheral organs and receptors can be damaged during tumor progression, and P2X7R expression in nerve cells (such as microglia) is significantly upregulated, enhancing sensory afferent information, sensitizing the central nervous system, and inducing or exacerbating pain. These findings reveal that the ATP-P2X7R signaling axis plays a key regulatory role in the pathogenesis of tumors and cancer pain and also has a therapeutic role. Accordingly, in this study, we explored the role of P2X7R in tumors and cancer pain, discussed the pharmacological properties of inhibiting P2X7R activity (such as the use of antagonists) or blocking its expression in the treatment of tumor and cancer pain, and provided an important evidence for the treatment of both in the future.

Over the past decade, there has been a notable increase in research on sphingosine-1-phosphate receptor 2 (S1PR2), which is a type of G-protein-coupled receptor. Upon activation by S1P or other ligands, S1PR2 initiates downstream signaling pathways such as phosphoinositide 3-kinase (PI3K), Mitogen-activated protein kinase (MAPK), Rho/Rho-associated coiled-coil containing kinases (ROCK), and others, contributing to the diverse biological functions of S1PR2 and playing a pivotal role in various physiological processes and disease progressions, such as multiple sclerosis, fibrosis, inflammation, and tumors. Due to the extensive biological functions of S1PR2, many S1PR2 modulators, including agonists and antagonists, have been developed and discovered by pharmaceutical companies (e.g., Novartis and Galapagos NV) and academic medicinal chemists for disease diagnosis and treatment. However, few reviews have been published that comprehensively overview the functions and regulators of S1PR2. Herein, we provide an in-depth review of the advances in the function of S1PR2 and its modulators. We first summarize the structure and biological function of S1PR2 and its pathological role in human diseases. We then focus on the discovery approach, design strategy, development process, and biomedical application of S1PR2 modulators. Additionally, we outline the major challenges and future directions in this field. Our comprehensive review will aid in the discovery and development of more effective and clinically applicable S1PR2 modulators.

Transient receptor potential vanilloid 1 (TRPV1) is a transmembrane and non-selective cation channel protein, which can be activated by various physical and chemical stimuli. Recent studies have shown the strong pathogenetic associations of TRPV1 with neurodegenerative diseases (NDs), in particular Alzheimer\'s disease (AD), Parkinson\'s disease (PD) and multiple sclerosis (MS) via regulating neuroinflammation. Therapeutic effects of TRPV1 agonists and antagonists on the treatment of AD and PD in animal models also are emerging. We here summarize the current understanding of TRPV1\'s effects and its agonists and antagonists as a therapeutic means in neurodegenerative diseases, and highlight future treatment strategies using natural TRPV1 agonists. Developing new targets and applying natural products are becoming a promising direction in the treatment of chronic disorders, especially neurodegenerative diseases.

More and more studies have revealed that P2 purinergic receptors play a key role in the progression of colorectal cancer (CRC). P2X and P2Y purinergic receptors can be used as promoters and regulators of CRC and play a dual role in the progression of CRC. CRC microenvironment is rich in ATP and its cleavage products (ADP, AMP, Ado), which act as activators of P2X and P2Y purinergic receptors. The activation of P2X and P2Y purinergic receptors regulates the progression of CRC mainly by regulating the function of immune cells and mediating different signal pathways. In this paper, we focus on the specific mechanisms and functional roles of P2X7, P2Y12, and P2Y2 receptors in the growth and progression of CRC. The antagonistic effects of these selective antagonists of P2X purinergic receptors on the growth, invasion, and metastasis of CRC were further discussed. Moreover, different studies have reported that P2X7 receptor can be used as an effective predictor of patients with CRC. All these indicate that P2 purinergic receptors are a key regulator of CRC. Therefore, antagonizing P2 purinergic receptors may be an innovative treatment for CRC.

The Adenosine A2B receptor (A2BAR) is considered a novel potential target for the immunotherapy of cancer, and A2BAR antagonists have an inhibitory effect on tumor growth, proliferation, and metastasis. In our previous studies, we identified a class of benzimidazole-pyrazine scaffolds whose derivatives exhibited the antagonistic effect but lacked subtype selectivity towards A2BAR. In this work, we developed a scaffold-based protocol that incorporates a deep generative model and multilayer virtual screening to design benzimidazole-pyrazine derivatives as potential selective A2BAR antagonists. By utilizing a generative model with reported A2BAR antagonists as the training set, we built up a scaffold-focused library of benzimidazole-pyrazine derivatives and processed a virtual screening protocol to discover potential A2BAR antagonists. Finally, five molecules with different Bemis-Murcko scaffolds were identified and exhibited higher binding free energies than the reference molecule 12o. Further computational analysis revealed that the 3-benzyl derivative ABA-1266 presented high selectivity toward A2BAR and showed preferred draggability, providing future potent development of selective A2BAR antagonists.Communicated by Ramaswamy H. Sarma.

Neurodegenerative diseases seriously affect patients\' physical and mental health, reduce their quality of life, and impose a heavy burden on society. However, their treatment remains challenging. Therefore, exploring factors potentially related to the pathogenesis of neurodegenerative diseases and improving their diagnosis and treatment are urgently needed. Recent studies have shown that P2 × 7R plays a crucial role in regulating neurodegenerative diseases caused by neuroinflammation. P2 × 7R is an adenosine 5\'-triphosphate ligand-gated cation channel receptor present in most tissues of the human body. An increase in P2 × 7R levels can affect the progression of neurodegenerative diseases, and the inhibition of P2 × 7R can alleviate neurodegenerative diseases. In this review, we comprehensively describe the biological characteristics (structure, distribution, and function) of this gene, focusing on its potential association with neurodegenerative diseases, and we discuss the pharmacological effects of drugs (P2 × 7R inhibitors) used to treat neurodegenerative diseases.