Neuropathic pain, a common symptom of several disorders, exerts a substantial socioeconomic burden worldwide. Transient receptor potential vanilloid 1 (TRPV1), a non-selective cation channel predominantly ex-pressed in nociceptive neurons, plays a pivotal role in nociception, by detecting various endogenous and exogenous stimuli, including heat, pro-inflammatory mediators, and physical stressors. Dysregulation of TRPV1 signaling further contributes to the pathophysiology of neuropathic pain. Therefore, targeting TRPV1 is a promising strategy for developing novel analgesics with improved efficacy and safety profiles. Several pharmacological approaches to modulate TRPV1 activity, including agonists, antagonists, and biological TRPV1 RNA interference (RNAi, small interfering RNA [siRNA]) have been explored. Despite preclinical success, the clinical translation of TRPV1-targeted therapies has encountered challenges, including hyperthermia, hypothermia, pungency, and desensitization. Nevertheless, ongoing research efforts aim to refine TRPV1-targeted interventions through structural modifications, development of selective modulators, and discovery of natural, peptide-based drug candidates. Herein, we provide guidance for researchers and clinicians involved in the development of new interventions specifically targeting TRPV1 by reviewing the existing literature and highlighting current research activities. This study further discusses potential future research endeavors for enhancing the efficacy, safety, and tolerability of TRPV1 candidates, and thereby facilitates the translation of these discoveries into effective clinical interventions to alleviate neuropathic pain disorders.

Chronic obstructive pulmonary disease(COPD) is a gradually worsening and fatal heterogeneous lung disease characterized by airflow limitation and increasingly decline in lung function. Currently, it is one of the leading causes of death worldwide. The consistent feature of COPD is airway inflammation. Several inflammatory factors are known to be involved in COPD pathogenesis; however, anti-inflammatory therapy is not the first-line treatment for COPD. Although bronchodilators, corticosteroids and roflumilast could improve airflow and control symptoms, they could not reverse the disease. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway plays an important novel role in the immune system and has been confirmed to be a key mediator of inflammation during infection, cellular stress, and tissue damage. Recent studies have emphasized that abnormal activation of cGAS-STING contributes to COPD, providing a direction for new treatments that we urgently need to develop. Here, we focused on the cGAS-STING pathway, providing insight into its molecular mechanism and summarizing the current knowledge on the role of the cGAS-STING pathway in COPD. Moreover, we explored antagonists of cGAS and STING to identify potential therapeutic strategies for COPD that target the cGAS-STING pathway.

The effective management of moderate to severe pain often relies on the use of analgesic agents. However, the widespread utility of these medications is hindered by the occurrence of several undesirable side effects. In light of this challenge, there is growing interest in the development of κ opioid receptor (KOR) agonists, which have shown promise in mitigating these adverse effects. In this study, leveraging the structural scaffold of compound D (our previous study), we embarked on the design, synthesis, and evaluation of a series of N\'-benzyl-3-chloro-N- ((1S,3R,4R)-3-((dimethylamino)methyl)-4-hydroxy-4-(3-methoxyphenyl)cyclohexyl)benzenesulfonamide derivatives. These compounds were subjected to comprehensive in vitro and in vivo test. Through systematic structure-activity relationship (SAR) exploration, we successfully identified compound 23p (Ki(KOR):1.9 nM) as a highly selective KOR ligand of new chemotype. 23p showed high clearance in vitro PK test, and abdominal contraction test showed potent antinociceptive effect. 23p and its O-demethyl metabolite 25 were both found in the plasma of mouse, 25 also showed potent affinity toward KOR (Ki(KOR): 3.1 nM), both they contribute to the analgesic effect. Moreover, 23p exhibited potent antinociceptive activity in abdominal constriction test, which was effectively abolished by pre-treatment of nor-BNI, a selective KOR antagonist.

The Frizzleds (FZDs) receptors on the cell surface belong to the class F of G protein-coupled receptors (GPCRs) which are the major receptors of WNT protein that mediates the classical WNT signaling pathway and other non-classical pathways. Besides, the FZDs also play a core role in tissue regeneration and tumor occurrence. With the structure and mechanism of FZDs activation becoming clearer, a series of FZDs modulators (inhibitors and agonists) have been developed, with the hope of bringing benefits to the treatment of cancer and degenerative diseases. Most of the FZDs inhibitors (small molecules, antibodies or designed protein inhibitors) block WNT signaling through binding to the cysteine-rich domain (CRD) of FZDs. Several small molecules impede FZDs activation by targeting to the third intracellular domain or the transmembrane domain of FZDs. However, three small molecules (FZM1.8, SAG1.3 and purmorphamine) activate the FZDs through direct interaction with the transmembrane domain. Another type of FZDs agonists are bivalent or tetravalent antibodies which activate the WNT signaling via inducing FZD-LRP5/6 heterodimerization. In this article, we reviewed the FZDs modulators reported in recent years, summarized the critical molecules\' discovery processes and the elucidated relevant structural and pharmacological mechanisms. We believe the summaried molecular mechanisms of the relevant modulators could provide important guidance and reference for the future development of FZD modulators.

Trace Amine Associated Receptor 1 (TAAR1) is a novel pharmaceutical target under investigation for the treatment of several neuropsychiatric conditions. TAAR1 single nucleotide variants (SNV) have been found in patients with schizophrenia and metabolic disorders. However, the frequency of variants in geographically diverse populations and the functional effects of such variants are unknown. In this study, we aimed to characterise the distribution of TAAR1 SNVs in five different WHO regions using the Database of Genotypes and Phenotypes (dbGaP) and conducted a critical computational analysis using available TAAR1 structural data to identify SNVs affecting ligand binding and/or functional regions. Our analysis shows 19 orthosteric, 9 signalling and 16 micro-switch SNVs hypothesised to critically influence the agonist induced TAAR1 activation. These SNVs may non-proportionally influence populations from discrete regions and differentially influence the activity of TAAR1-targeting therapeutics in genetically and geographically diverse populations. Notably, our dataset presented with orthosteric SNVs D1033.32N (found only in the South-East Asian Region and Western Pacific Region) and T1945.42A (found only in South-East Asian Region), and 2 signalling SNVs (V1253.54A/T2526.36A, found in African Region and commonly, respectively), all of which have previously demonstrated to influence ligand induced functions of TAAR1. Furthermore, bioinformatics analysis using SIFT4G, MutationTaster 2, PROVEAN and MutationAssessor predicted all 16 micro-switch SNVs are damaging and may further influence the agonist activation of TAAR1, thereby possibly impacting upon clinical outcomes. Understanding the genetic basis of TAAR1 function and the impact of common mutations within clinical populations is important for the safe and effective utilisation of novel and existing pharmacotherapies.

Forty percent of Americans are obese and 20% are overweight. Until recently, notwithstanding great efforts to combat this chronic, worsening epidemic, the only therapy that \"worked\" was surgery. However, recently, a new class of safe drugs (incretins) have been developed that cause obese patients to lose ∼20 to 25% of their body weight. Herein we recount this revolution and its implications.

Retinoic acid-related orphan receptors (RORs) serve as transcription factors that play a pivotal role in a myriad of physiological processes within the body. Their involvement extends to critical biological processes that confer protective effects in the heart, immune system, and nervous system, as well as contributing to the mitigation of several aggressive cancer types. These protective functions are attributed to ROR\'s regulation of key proteins and the management of various cellular processes, including autophagy, mitophagy, inflammation, oxidative stress, and glucose metabolism, highlighting the emerging need for pharmacological approaches to modulate ROR expression. Thus, the modulation of RORs is a rapidly growing area of research aimed not only at comprehending these receptors, but also at manipulating them to attain the desired physiological response. Despite the presence of natural ROR ligands, the development of synthetic agonists with high selectivity for these receptors holds substantial therapeutic potential. The exploration and advancement of such compounds can effectively target diseases associated with ROR dysregulation, thereby providing avenues for therapeutic interventions. Herein, we provide a comprehensive examination of the multifaceted role of ROR in diverse physiological and pathophysiological conditions, accompanied by an in-depth exploration of a spectrum of ROR agonists, inverse agonists, and antagonists.

The search for melatonin receptor agonists formed the main part of melatonin medicinal chemistry programs for the last three decades. In this short review, we summarize the two main aspects of these programs: the development of all the necessary tools to characterize the newly synthesized ligands at the two melatonin receptors MT1 and MT2, and the medicinal chemist\'s approaches to find chemically diverse ligands at these receptors. Both strategies are described. It turns out that the main source of tools were industrial laboratories, while the medicinal chemistry was mainly carried out in academia. Such complete accounts are interesting, as they delineate the spirits in which the teams were working demonstrating their strength and innovative character. Most of the programs were focused on nonselective agonists and few of them reached the market. In contrast, discovery of MT1-selective agonists and melatonergic antagonists with proven in vivo activity and MT1 or MT2-selectivity is still in its infancy, despite the considerable interest that subtype selective compounds may bring in the domain, as the physiological respective roles of the two subtypes of melatonin receptors, is still poorly understood. Poly-pharmacology applications and multitarget ligands have also been considered.

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.

Transition-metal-catalyzed [4+4] cycloaddition leading to cyclooctanoids has centered on dimerization between 1,3-diene-type substrates. Herein, we describe a [4σ+4π-1] and [4σ+4π] cycloaddition strategy to access 7/8-membered fused carbocycles through rhodium-catalyzed coupling between the 4σ-donor (benzocyclobutenones) and pendant diene (4π) motifs. The two pathways can be controlled by adjusting the solvated CO concentration. A broad range (>40 examples) of 5-6-7 and 5-6-8 polyfused carbocycles was obtained in good yields (up to 90 %). DFT calculations, kinetic monitoring and 13C-labeling experiments were carried out, suggesting a plausible mechanism. Notably, one 5-6-7 tricycle was found to be a very rare, potent, and selective ligand for the liver X receptor β (KD=0.64 μM), which is a potential therapeutic target for cholesterol-metabolism-related fatal diseases.