UNASSIGNED: The neuropeptide relaxin-3/RXFP3 system belongs to the relaxin/insulin superfamily and is involved in many important physiological processes, such as stress responses, appetite control, and motivation for reward. Although relaxin-3 is the endogenous agonist for RXFP3, it can also bind to and activate RXFP1 and RXFP4. Consequently, research has been focused on the development of RXFP3-specific peptides and small-molecule ligands to validate the relaxin-3/RXFP3 system as a novel drug target.
UNASSIGNED: This review provides an overview of patents on the relaxin-3/RXFP3 system covering ligand development and pharmacological studies since 2003. Related patents and literature reports were obtained from established sources including SciFinder, Google Patents, and Espacenet for patents and SciFinder, PubMed, and Google Scholar for literature reports.
UNASSIGNED: There has been an increasing amount of patent activities around relaxin-3/RXFP3, highlighting the importance of this novel neuropeptide system for drug discovery. The development of relaxin-3 derived peptides and small-molecule modulators, as well as behavioral studies in rodents, have shown that the relaxin-3/RXFP3 system is a promising drug target for treating various metabolic and neuropsychiatric diseases including obesity, anxiety, and alcohol addiction.

Colorectal cancer (CRC) stands as one of the most prevalent form of cancer globally, causing a significant number of deaths, surpassing 0.9 million in the year 2020. According to GLOBOCAN 2020, CRC ranks third in incidence and second in mortality in both males and females. Despite extensive studies over the years, there is still a need to establish novel therapeutic targets to enhance the patients\' survival rate in CRC. Nuclear receptors (NRs) are ligand-activated transcription factors (TFs) that regulate numerous essential biological processes such as differentiation, development, physiology, reproduction, and cellular metabolism. Dysregulation and anomalous expression of different NRs has led to multiple alterations, such as impaired signaling cascades, mutations, and epigenetic changes, leading to various diseases, including cancer. It has been observed that differential expression of various NRs might lead to the initiation and progression of CRC, and are correlated with poor survival outcomes in CRC patients. Despite numerous studies on the mechanism and role of NRs in this cancer, it remains of significant scientific interest primarily due to the diverse functions that various NRs exhibit in regulating key hallmarks of this cancer. Thus, modulating the expression of NRs with their agonists and antagonists, based on their expression levels, holds an immense prospect in the diagnosis, prognosis, and therapeutical modalities of CRC. In this review, we primarily focus on the role and mechanism of NRs in the pathogenesis of CRC and emphasized the significance of targeting these NRs using a variety of agents, which may represent a novel and effective strategy for the prevention and treatment of this cancer.

Toll-like receptors 3 (TLR3) have been broadly studied among all TLRs over the last few decades together with its agonists due to their contribution to cancer regression. These agonists undeniably have some shared characteristics such as mimicking dsRNA but pathways through which they exhibit antitumor properties are relatively diverse. In this review, three widely studied agonists RGC100, ARNAX, and poly-IC are discussed along with their structural and physiochemical differences including the signaling cascades through which they exert their actions. Comparison has been made to identify the finest agonist with maximum effectivity and the least side effect profile.

UNASSIGNED: Stimulator of interferon genes (STING) is a transmembrane protein that localizes in the endoplasmic reticulum. As a crucial adaptor protein in the pathway of sensing cytosolic DNA, STING can regulate innate immune response by inducing the secretion of type Ι interferons and other cytokines after recognizing endogenous or exogenous DNA. Due to the key role of STING in the innate immune system, activation of the STING signaling pathway is expected to be an efficacious immunotherapeutic tactic for cancer and infectious diseases caused by pathogens.
UNASSIGNED: This review summarizes the structures and biological activities of STING agonists published from 2008 to present, the progress in its structural modification of STING agonists, and the development of their clinical study.
UNASSIGNED: STING is an important adaptor protein in the process of triggering the innate immune response to viral infection. So far, substantial STING agonists and inhibitors have been published, and their viable curative effects for diverse diseases prove that STING is a promising therapeutic target.

Stimulator of interferon genes (STING) plays a crucial role in human innate immune system, which is gradually concerned following the emerging immunotherapy. Activated STING induces the production of type I interferons (IFNs) and proinflammatory cytokines through STING-TBK1-IRF3/NF-κB pathway, which could be applied into the treatment of infection, inflammation, and tumorigenesis. Here, we provided a detailed summary of STING from its structure, function and regulation. Especially, we illustrated the canonical or noncanonical cyclic dinucleotides (CDNs) and synthetic small molecules for STING activation or inhibition and their efficacy in related diseases. Importantly, we particularly emphasized the discovery, development and modification of STING agonist or antagonist, attempting to enlighten reader\'s mind for enriching small molecular modulator of STING. In addition, we summarized biological evaluation methods for the assessment of small molecules activity.

The known seven mammalian receptor subunits (P2X1-7) form cationic channels gated by ATP. Three subunits compose a receptor channel. Each subunit is a polypeptide consisting of two transmembrane regions (TM1 and TM2), intracellular N- and C-termini, and a bulky extracellular loop. Crystallization allowed the identification of the 3D structure and gating cycle of P2X receptors. The agonist-binding pocket is located at the intersection of two neighbouring subunits. In addition to the mammalian P2X receptors, their primitive ligand-gated counterparts with little structural similarity have also been cloned. Selective agonists for P2X receptor subtypes are not available, but medicinal chemistry supplied a range of subtype-selective antagonists, as well as positive and negative allosteric modulators. Knockout mice and selective antagonists helped to identify pathological functions due to defective P2X receptors, such as male infertility (P2X1), hearing loss (P2X2), pain/cough (P2X3), neuropathic pain (P2X4), inflammatory bone loss (P2X5), and faulty immune reactions (P2X7).

Enzymatic cleavage of endogenous peptides is a commonly used principle to initiate, modulate and terminate action for instance among cytokines and peptide hormones. The incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), and the related hormone glucagon-like peptide-2 (GLP-2) are all rapidly N-terminally truncated with severe loss of intrinsic activity. The most abundant circulating form of full length GIP(1-42) is GIP(3-42) (a dipeptidyl peptidase-4 (DPP-4) product). GIP(1-30)NH2 is another active form resulting from prohormone convertase 2 (PC2) cleavage of proGIP. Like GIP(1-42), GIP(1-30)NH2 is a substrate for DPP-4 generating GIP(3-30)NH2 which, compared to GIP(3-42), binds with higher affinity and very efficiently inhibits GIP receptor (GIPR) activity with no intrinsic activity. Here, we review the action of these four and multiple other N- and C-terminally truncated forms of GIP with an emphasis on molecular pharmacology, i.e. ligand binding, subsequent receptor activation and desensitization. Our overall conclusion is that the N-terminus is essential for receptor activation as GIP N-terminal truncation leads to decreased/lost intrinsic activity and antagonism (similar to GLP-1 and GLP-2), whereas the C-terminal extension of GIP(1-42), as compared to GLP-1, GLP-2 and glucagon (29-33 amino acids), has no apparent impact on the GIPR in vitro, but may play a role for other properties such as stability and tissue distribution. A deeper understanding of the molecular interaction of naturally occurring and designed GIP-based peptides, and their impact in vivo, may contribute to a future therapeutic targeting of the GIP system - either with agonists or with antagonists, or both.

After a Turkish scientist took Nobel Prize due to his contributions to understand clock genes, melatonin, closely related to these genes, may begin to shine. Melatonin, a hormone secreted from the pineal gland at night, plays roles in regulating sleep-wake cycle, pubertal development and seasonal adaptation. Melatonin has antinociceptive, antidepressant, anxiolytic, antineophobic, locomotor activity-regulating, neuroprotective, anti-inflammatory, pain-modulating, blood pressure-reducing, retinal, vascular, anti-tumor and antioxidant effects. It is related with memory, ovarian physiology, and osteoblast differentiation. Pathologies associated with an increase or decrease in melatonin levels are summarized in the review. Melatonin affects by four mechanisms: 1) Binding to melatonin receptors in plasma membrane, 2) Binding to intracellular proteins such as calmoduline, 3) Binding to Orphan nuclear receptors, and 4) Antioxidant effect. Receptors associated with melatonin are as follows: 1) Melatonin receptor type 1a: MT1 (on cell membrane), 2) Melatonin receptor type 1b: MT2 (on cell membrane), 3) Melatonin receptor type 1c (found in fish, amphibians and birds), 4) Quinone reductase 2 enzyme (MT3 receptor, a detoxification enzyme), 5) RZR/RORα: Retinoid-related Orphan nuclear hormone receptor (with this receptor, melatonin binds to the transcription factors in nucleus), and 6) GPR50: X-linked Melatonin-related Orphan receptor (it is effective in binding of melatonin to MT1). Melatonin agonists such as ramelteon, agomelatine, circadin, TIK-301 and tasimelteon are introduced and side effects will be discussed. In conclusion, melatonin and related drugs is a new and promising era for medicine. Melatonin receptors and melatonin drugs will take attention with greater interest day by day in the future.
Saat genlerini anlamamıza olan katkısından dolayı bir Türk bilim adamı Nobel ödülünü aldıktan sonra, bu genlerle yakın ilişkili olan melatoninin önemi arttı. Melatonin, pineal bezden gece salınan bir hormondur, uyku/uyanıklık döngüsünde, pubertal gelişimde ve mevsimsel adaptasyonda rol alır. Melatoninin antinosiseptif, antidepresan, anksiyolitik, antineofobik, locomotor aktiviteyi düzenleyici, nöroprotektif, antiinflamatuvar, ağrı düzenleyici, kan basıncını düşürücü, retinal, vasküler, tümör baskılayıcı ve antioksidan etkileri vardır. Hafıza, over fizyolojisi ve osteoblast diferansiasyonuyla ilişkilidir. Melatonin seviyelerinde artış veya azalışla seyreden patolojiler derlemede özetlenmiştir. Melatonin 4 mekanizmayla etkir: 1) Plazma membranında melatonin reseptörlerine bağlanma, 2) Kalmodulin gibi hücre içi reseptörlere bağlanma, 3) Yetim nükleer reseptörlere bağlanma, 4) Antioksidan etkiler. Melatoninle ilişkili reseptörler şunlardır: 1) Melatonin reseptör tip1a: MT1 (hücre zarında), 2) Melatonin reseptör tip1b: MT2 (hücre zarında), 3) Melatonin reseptör tip1c (balık, amfibiler ve kuşlarda bulunur), 4) Kuinon redüktaz-2 enzimi (MT3 reseptörü, bir detoksifikasyon enzimi), 5) RZR/RORα: Retinoid-ilişkili Yetim çekirdek hormon reseptörü (bu reseptörle melatonin çekirdekte transkripsiyon faktörlerine bağlanır), 6) GPR50: X-geçişli Melatonin-ilişkili yetim reseptör (melatoninin MT1’e bağlanmasında etkilidir). Ramelteon, agomelatin, sirkadin, TIK-301 and tasimelteon gibi Melatonin agonistleri tanıtılacak ve yan etkileri karşılaştırılacaktır. Sonuçta, melatonin ve ilişkili ilaçlar tıpta yeni ve umut vaat eden bir alandır. Melatonin reseptörleri ve ilaçları gelecekte de artan oranda ilgi çekmeye devam edecektir.

BACKGROUND: Serotonin or 5-hydroxytryptamine (5-HT) is a substance found in plasma, which increases smooth muscle contraction and mediates platelet aggregation. In addition, it is a monoamine neurotransmitter and is implicated in diverse behaviors. The serotonin receptor 2 (5-HT2) subfamily is best known for biased signaling and is strongly expressed mainly in the brain regions postulated to be involved in the modulation of higher cognitive and affective functions. Modulators of the 5-HT2 receptor are currently used to treat a variety of diseases including chronic pain and psychonosema. These properties suggest that 5-HT2 receptors may become an important therapeutic target for the treatment of various pathological conditions.
METHODS: This review highlights the significant progress that has been made in the discovery and development of 5-HT2 receptor agonists and antagonists based on an analysis of the patent literature between January 2004 and December 2014.
CONCLUSIONS: Cumulative evidence over the past decade supports the notion that the modulation of 5-HT2 receptors has a positive effect on human cognition and emotion. Therefore, we suggest that new agonists and antagonists may play an important role in the treatment of disorders such as schizophrenia, addiction and obesity.