Cancer Cells Show Higher Sensitivity to Melatonin-Tamoxifen Drug Conjugates than to Combination of Melatonin and Tamoxifen.

Drug conjugates of tamoxifen and melatonin linked through the amide side chain of melatonin (,) were reported as promising agents for future treatment of breast cancer, possibly reversing the adverse effects of tamoxifen. Here, we report the synthesis and pharmacological evaluation of a novel series of anticancer drug conjugates linking melatonin with tamoxifen through polymethylene spacers through the ether oxygen of melatonin (-, -, ) and compare them to the previously reported amide-linked analogues and . All hybrid ligands are antagonists of estrogen receptor alpha and agonists of the melatonin MT receptor with variable potencies.

Melatonin receptor structure and signaling.

Melatonin (5-methoxy-N-acetyltryptamine) binds with high affinity and specificity to membrane receptors. Several receptor subtypes exist in different species, of which the mammalian MT and MT receptors are the best-characterized. They are members of the G protein-coupled receptor superfamily, preferentially coupling to G proteins but also to other G proteins in a cell-context-depending manner.

2023 Julius Axelrod Symposium: Plant-Derived Molecules Acting on G Protein-Coupled Receptors.

Plant extracts have played a significant role in traditional medicine for centuries, contributing to improved health and the treatment of various human illnesses. G protein-coupled receptors (GPCRs) are crucial in numerous physiologic functions, and there is growing evidence suggesting their involvement in the therapeutic effects of many plant extracts. In recent years, scientists have identified an expanding number of isolated molecules responsible for the biologic activity of these extracts, with many believed to act on GPCRs.

Simufilam Reverses Aberrant Receptor Interactions of Filamin A in Alzheimer's Disease.

Simufilam is a novel oral drug candidate in Phase 3 clinical trials for Alzheimer's disease (AD) dementia. This small molecule binds an altered form of filamin A (FLNA) that occurs in AD. This drug action disrupts FLNA's aberrant linkage to the α7 nicotinic acetylcholine receptor (α7nAChR), thereby blocking soluble amyloid beta (Aβ)'s signaling via α7nAChR that hyperphosphorylates tau.

Mitochondria-targeted melatonin photorelease supports the presence of melatonin MT1 receptors in mitochondria inhibiting respiration.

The presence of signaling-competent G protein-coupled receptors in intracellular compartments is increasingly recognized. Recently, the presence of G protein-coupled melatonin MT receptors in mitochondria has been revealed, in addition to the plasma membrane. Melatonin is highly cell permeant, activating plasma membrane and mitochondrial receptors equally.

Extract Potentiates the Effect of Melatonin on Human Melatonin MT and MT Receptors with Functional Selectivity.

Melatonin is a tryptophan derivative synthesized in plants and animals. In humans, melatonin acts on melatonin MT and MT receptors belonging to the G protein-coupled receptor (GPCR) family. Synthetic melatonin receptor agonists are prescribed for insomnia and depressive and circadian-related disorders.

Melatonin: Facts, Extrapolations and Clinical Trials.

Melatonin is a fascinating molecule that has captured the imagination of many scientists since its discovery in 1958. In recent times, the focus has changed from investigating its natural role as a transducer of biological time for physiological systems to hypothesized roles in virtually all clinical conditions. This goes along with the appearance of extensive literature claiming the (generally) positive benefits of high doses of melatonin in animal models and various clinical situations that would not be receptor-mediated.

Melatonin-vorinostat hybrid ligands show higher histone deacetylase and cancer cell growth inhibition than vorinostat.

Anticancer drug conjugates are an emerging approach for future cancer treatment. Here, we report a series of hybrid ligands merging the neurohormone melatonin with the approved histone deacetylase (HDAC) inhibitor vorinostat, using melatonin's amide side chain (3a-e), its indolic nitrogen (5a-d), and its ether oxygen (7a-d) as attachment points. Several hybrid ligands showed higher potency thanvorinostat in both HDAC inhibition and cellular assays on different cultured cancer cell lines.

A seeding-based neuronal model of tau aggregation for use in drug discovery.

Intracellular accumulation of tau protein is a hallmark of Alzheimer's Disease and Progressive Supranuclear Palsy, as well as other neurodegenerative disorders collectively known as tauopathies. Despite our increasing understanding of the mechanisms leading to the initiation and progression of tau pathology, the field still lacks appropriate disease models to facilitate drug discovery. Here, we established a novel and modulatable seeding-based neuronal model of full-length 4R tau accumulation using humanized mouse cortical neurons and seeds from P301S human tau transgenic animals.

Novel repertoire of tau biosensors to monitor pathological tau transformation and seeding activity in living cells.

Aggregates of the tau protein are a well-known hallmark of several neurodegenerative diseases, collectively referred to as tauopathies, including frontal temporal dementia and Alzheimer's disease (AD). Monitoring the transformation process of tau from physiological monomers into pathological oligomers or aggregates in a high-throughput, quantitative manner and in a cellular context is still a major challenge in the field. Identifying molecules able to interfere with those processes is of high therapeutic interest.

Development of indolealkylamine derivatives as potential multi-target agents for COVID-19 treatment.

COVID-19 is a complex disease with short-term and long-term respiratory, inflammatory and neurological symptoms that are triggered by the infection with SARS-CoV-2. As many drugs targeting single targets showed only limited effectiveness against COVID-19, here, we aimed to explore a multi-target strategy. We synthesized a focused compound library based on C2-substituted indolealkylamines (tryptamines and 5-hydroxytryptamines) with activity for three potential COVID-19-related proteins, namely melatonin receptors, calmodulin and human angiotensin converting enzyme 2 (hACE2).

Homocysteine causes neuronal leptin resistance and endoplasmic reticulum stress.

Abnormally high serum homocysteine levels have been associated with several disorders, including obesity, cardiovascular diseases or neurological diseases. Leptin is an anti-obesity protein and its action is mainly mediated by the activation of its Ob-R receptor in neuronal cells. The inability of leptin to induce activation of its specific signaling pathways, especially under endoplasmic reticulum stress, leads to the leptin resistance observed in obesity.

Measuring Protein-Protein Interactions of Melatonin Receptors by Bioluminescence Resonance Energy Transfer (BRET).

The melatonin receptor subfamily belongs to the G protein-coupled receptor superfamily and consists of three members in mammals, MT, MT, and GPR50. These receptors can interact with each other to form homo- and heterodimers that are part of larger molecular complexes composed of G proteins, β-arrestins, and other membrane and cytosolic proteins. BRET (bioluminescence resonance energy transfer) is a versatile technique to follow protein-protein interactions on the nanometer scale, in real time, in living cells, which contributed largely to our understanding of the function of melatonin receptors.

Functional Investigation of Melatonin Receptor Activation by Homogenous cAMP Assay.

Cyclic adenosine monophosphate (cAMP) is an important ubiquitous second messenger and one of the major pathways transducing the activation of G protein-coupled receptors (GPCRs). Quantifying intracellular levels of cAMP in an accurate and high-throughput manner is, therefore, of high interest to access functional responses of GPCRs. The neurohormone melatonin is selectively recognized by two GPCRs in mammals, named MT and MT.

GTPγS Binding Assay for Melatonin Receptors in Mouse Brain Tissue.

The [S]GTPγS assay is a method that measures the level of G protein activation by determining the binding of [S]GTPγS, a non-hydrolyzable and radioactively labeled GTP analog, to Gα subunit of heterotrimeric G protein upon activation of G protein-coupled receptors (GPCR). The power of this assay lies in the fact that it measures an early event of GPCR signaling in cells expressing recombinant receptors and cells and tissues expressing endogenous receptors. The present protocol describes a sensitive method for studying G protein activation by melatonin receptors MT and MT, in membranes prepared from mouse brain.

2-[I]iodomelatonin and [H]melatonin Binding Assays for Melatonin Receptors.

The radioligand binding assay is a powerful method to study the interaction of a ligand with its target. This technique allows not only to determine different pharmacological key parameters such as the affinity and the association and dissociation constants but also to estimate the amount of target expressed in recombinant or endogenous cells or tissues. The current detailed protocols describe the different binding assays (saturation, kinetic, and competition) that can be performed on melatonin receptors using their most commonly used and validated radioligands 2-[I]-iodomelatonin (2-[I]-MLT) and [H]-melatonin ([H]-MLT).