Industrial and academic approaches to the search for alternative melatonin receptor ligands: An historical survey.

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 MT and MT, and the medicinal chemist's approaches to find chemically diverse ligands at these receptors. Both strategies are described.

Binding and unbinding of potent melatonin receptor ligands: Mechanistic simulations and experimental evidence.

The labeled ligand commonly employed in competition binding studies for melatonin receptor ligands, 2-[I]iodomelatonin, showed slow dissociation with different half-lives at the two receptor subtypes. This may affect the operational measures of affinity constants, which at short incubation times could not be obtained in equilibrium conditions, and structure-activity relationships, as the K values of tested ligands could depend on either interaction at the binding site or the dissociation path. To address these issues, the kinetic and saturation binding parameters of 2-[I]iodomelatonin as well as the competition constants for a series of representative ligands were measured at a short (2 h) and a long (20 h) incubation time.

NAAA-regulated lipid signaling in monocytes controls the induction of hyperalgesic priming in mice.

Circulating monocytes participate in pain chronification but the molecular events that cause their deployment are unclear. Using a mouse model of hyperalgesic priming (HP), we show that monocytes enable progression to pain chronicity through a mechanism that requires transient activation of the hydrolase, N-acylethanolamine acid amidase (NAAA), and the consequent suppression of NAAA-regulated lipid signaling at peroxisome proliferator-activated receptor-α (PPAR-α). Inhibiting NAAA in the 72 hours following administration of a priming stimulus prevented HP.

2-Arylmelatonin analogues: Probing the 2-phenyl binding pocket of melatonin MT and MT receptors.

In crystal structures of melatonin MT and MT receptors, a lipophilic subpocket has been characterized which accommodates the phenyl ring of the potent agonist 2-phenylmelatonin. This subpocket appears a key structural element to achieve high binding affinity and selectivity for the MT receptor. A series of 2-arylindole ligands was synthesized to probe the requirements for the optimal occupation and interaction with the 2-phenyl binding pocket.

Radiosynthesis and Evaluation of Four Positron Emission Tomography Tracer Candidates for Imaging of Melatonin Receptors.

Melatonin is a neurohormone that modulates several physiological functions in mammals through the activation of melatonin receptor type 1 and 2 (MT and MT). The melatonergic system is an emerging therapeutic target for new pharmacological interventions in the treatment of sleep and mood disorders; thus, imaging tools to further investigate its role in the brain are highly sought-after. We aimed to develop selective radiotracers for imaging of both MT and MT by positron emission tomography (PET).

In silico drug discovery of melatonin receptor ligands with therapeutic potential.

Introduction: The neurohormone melatonin (-acetyl-5-methoxytryptamine) regulates circadian rhythms exerting a variety of effects in the central nervous system and in periphery. These activities are mainly mediated by activation of MT and MT GPCRs. MT/MT agonist compounds are used clinically for insomnia, depression, and circadian rhythm disturbances.

NAAA-regulated lipid signaling governs the transition from acute to chronic pain.

Chronic pain affects 1.5 billion people worldwide but remains woefully undertreated. Understanding the molecular events leading to its emergence is necessary to discover disease-modifying therapies.

N-(Anilinoethyl)amide Melatonergic Ligands with Improved Water Solubility and Metabolic Stability.

The MT -selective melatonin receptor ligand UCM765 (N-(2-((3-methoxyphenyl)(phenyl)amino)ethyl)acetamide), showed interesting sleep inducing, analgesic and anxiolytic properties in rodents, but suffers from low water solubility and modest metabolic stability. To overcome these limitations, different strategies were investigated, including modification of metabolically liable sites, introduction of hydrophilic substituents and design of more basic derivatives. Thermodynamic solubility, microsomal stability and lipophilicity of new compounds were experimentally evaluated, together with their MT and MT binding affinities.

Chemical modification of NSC12 leads to a specific FGF-trap with antitumor activity in multiple myeloma.

Inhibition of FGF/FGFR signaling is a promising strategy for the treatment of malignances dependent from FGF stimulation, including multiple myeloma (MM). The steroidal derivative NSC12 (compound 1) is a pan-FGF trap endowed with antitumor activity in vivo. Chemical modifications of compound 1 were explored to investigate structure-activity relationships, focusing on the role of the bis(trifluoromethyl)1,3-propanediol chain, the stereochemistry at C20 and functionalization of C3 position.

New classes of potent heparanase inhibitors from ligand-based virtual screening.

Heparanase is a validated target in cancer therapy and a potential target for several inflammatory pathologies. A ligand-based virtual screening of commercial libraries was performed to expand the chemical space of small-molecule inhibitors. The screening was based on similarity with known inhibitors and was performed in several runs, starting from literature compounds and progressing through newly discovered inhibitors.

Chiral Recognition of Flexible Melatonin Receptor Ligands Induced by Conformational Equilibria.

-anilinoethylamides are a class of melatoninergic agents with the aniline portion mimicking the indole ring of the natural ligand and the ethylamide chain reproducing that of melatonin. The simplest compound in this class, -{2-[(3-methoxyphenyl)methylamino]ethyl}acetamide (UCM793), has nanomolar binding affinity for MT and MT membrane receptors. To explore the effect of chain conformation on receptor binding, a methyl group was inserted on the methylene alpha or beta to the amide nitrogen and conformational equilibria were investigated by NMR spectroscopy and molecular dynamics simulations.

-Acylethanolamine Acid Amidase (NAAA): Structure, Function, and Inhibition.

-Acylethanolamine acid amidase (NAAA) is an N-terminal cysteine hydrolase primarily found in the endosomal-lysosomal compartment of innate and adaptive immune cells. NAAA catalyzes the hydrolytic deactivation of palmitoylethanolamide (PEA), a lipid-derived peroxisome proliferator-activated receptor-α (PPAR-α) agonist that exerts profound anti-inflammatory effects in animal models. Emerging evidence points to NAAA-regulated PEA signaling at PPAR-α as a critical control point for the induction and the resolution of inflammation and to NAAA itself as a target for anti-inflammatory medicines.

New Antimicrobials Targeting Bacterial RNA Polymerase Holoenzyme Assembly Identified with an BRET-Based Discovery Platform.

Bacterial resistance represents a major health threat worldwide, and the development of new therapeutics, including innovative antibiotics, is urgently needed. We describe a discovery platform, centered on screening and bioluminescence resonance energy transfer in yeast cells, for the identification of new antimicrobials that, by targeting the protein-protein interaction between the β'-subunit and the initiation factor σ of bacterial RNA polymerase, inhibit holoenzyme assembly and promoter-specific transcription. Out of 34 000 candidate compounds, we identified seven hits capable of interfering with this interaction.

Melatonin MT and MT Receptors Exhibit Distinct Effects in the Modulation of Body Temperature across the Light/Dark Cycle.

Melatonin (MLT) is a neurohormone that regulates many physiological functions including sleep, pain, thermoregulation, and circadian rhythms. MLT acts mainly through two G-protein-coupled receptors named MT and MT, but also through an MLT type-3 receptor (MT). However, the role of MLT receptor subtypes in thermoregulation is still unknown.

Design, Synthesis, and Biological Activity of Hydrogen Peroxide Responsive Arylboronate Melatonin Hybrids.

Stimulus-responsive cleavage reactions have found broad use to direct drug release at a particular target disease area. Increased levels of reactive oxygen species (ROS) have been associated with the development and progression of cancer and several other disease states, motivating the development of drug conjugates that can undergo a chemoselective ROS-triggered release. Melatonin (MLT) and the reactive electrophile p-benzoquinone methide ( p-QM) have evidenced either cytoprotective or cytotoxic effects in biological systems, depending on the dose, cellular targets, and time of exposure.

Identification of Bivalent Ligands with Melatonin Receptor Agonist and Fatty Acid Amide Hydrolase (FAAH) Inhibitory Activity That Exhibit Ocular Hypotensive Effect in the Rabbit.

Activation of melatonin receptors and inhibition of fatty acid amide hydrolase (FAAH) have both shown potential benefits for the treatment of glaucoma. To exploit the combination of these biological activities in single therapeutic agents, we designed dual-acting compounds sharing the pharmacophore elements required for the two targets, in search for balanced potencies as MT/MT agonists and FAAH inhibitors. In particular, the N-anilinoethylamide scaffold, previously developed for melatonergic ligands, was decorated at meta position with a polymethylene linker bound to an O-arylcarbamate group, substituted according to known structure-activity relationships for FAAH inhibition.

Tetrahydroquinoline Ring as a Versatile Bioisostere of Tetralin for Melatonin Receptor Ligands.

A new family of melatonin receptor ligands, characterized by a tetrahydroquinoline (THQ) scaffold carrying an amide chain in position 3, was devised as conformationally constrained analogs of flexible N-anilinoethylamides previously developed. Molecular superposition models allowed to identify the patterns of substitution conferring high receptor binding affinity and to support the THQ ring as a suitable scaffold for the preparation of melatonin ligands. The biological activity of 3-acylamino-THQs was compared with that of the corresponding tetralin derivatives.

Antiproliferative and pro-apoptotic activity of melatonin analogues on melanoma and breast cancer cells.

Melatonin plays different physiological functions ranging from the regulation of circadian rhythms to tumor inhibition, owing to its antioxidant, immunomodulatory and anti-aging properties. Due to its pleiotropic functions, melatonin has been shown to elicit cytoprotective processes in normal cells and trigger pro-apoptotic signals in cancer cells. The therapeutic potential of melatonin analogues prompted us to investigate the and antitumor activity of new melatonin derivatives and explore the underlying molecular mechanisms.

Cardioprotective effects of fatty acid amide hydrolase inhibitor URB694, in a rodent model of trait anxiety.

In humans, chronic anxiety represents an independent risk factor for cardiac arrhythmias and sudden death. Here we evaluate in male Wistar rats bred for high (HAB) and low (LAB) anxiety-related behavior, as well as non-selected (NAB) animals, the relationship between trait anxiety and cardiac electrical instability and investigate whether pharmacological augmentation of endocannabinoid anandamide-mediated signaling exerts anxiolytic-like and cardioprotective effects. HAB rats displayed (i) a higher incidence of ventricular tachyarrhythmias induced by isoproterenol, and (ii) a larger spatial dispersion of ventricular refractoriness assessed by means of an epicardial mapping protocol.

Antidepressant-like activity and cardioprotective effects of fatty acid amide hydrolase inhibitor URB694 in socially stressed Wistar Kyoto rats.

In humans, depression is often triggered by prolonged exposure to psychosocial stressors and is often associated with cardiovascular comorbidity. Mounting evidence suggests a role for endocannabinoid signaling in the regulation of both emotional behavior and cardiovascular function. Here, we examined cardiac activity in a rodent model of social stress-induced depression and investigated whether pharmacological inhibition of the enzyme fatty acid amide hydrolase (FAAH), which terminates signaling of the endocannabinoid anandamide, exerts antidepressant-like and cardioprotective effects.

Highly Potent and Selective MT2 Melatonin Receptor Full Agonists from Conformational Analysis of 1-Benzyl-2-acylaminomethyl-tetrahydroquinolines.

Molecular superposition models guided the design of novel melatonin receptor ligands characterized by a 2-acylaminomethyltetrahydroquinoline scaffold. Starting from the structure of N-anilinoethylamide ligands, the flexible chain was conformationally constrained to reproduce the bioactive conformation of melatonin. Structure-activity relationships were investigated, focusing on the substituent at the nitrogen atom, the position of the methoxy group, and the replacement of the amide side chain by urea and thiourea groups.

Pharmacokinetic and pharmacodynamic evaluation of ramelteon : an insomnia therapy.

Introduction: Ramelteon , a selective melatonin receptor agonist, is the first member of a novel class of hypnotics. It is approved for the treatment of insomnia characterized by sleep onset difficulties in the US and Japan, but not in Europe.

Areas Covered: The main clinical properties as well as safety issues of ramelteon are described.

Iridium-catalyzed direct synthesis of tryptamine derivatives from indoles: exploiting n-protected β-amino alcohols as alkylating agents.

The selective C3-alkylation of indoles with N-protected ethanolamines involving the "borrowing hydrogen" strategy is described. This method provides convenient and sustainable access to several tryptamine derivatives.

Selective melatonin MT2 receptor ligands relieve neuropathic pain through modulation of brainstem descending antinociceptive pathways.

Neuropathic pain is an important public health problem for which only a few treatments are available. Preclinical studies show that melatonin (MLT), a neurohormone acting on MT1 and MT2 receptors, has analgesic properties, likely through MT2 receptors. Here, we determined the effects of the novel selective MLT MT2 receptor partial agonist N-{2-([3-bromophenyl]-4-fluorophenylamino)ethyl}acetamide (UCM924) in 2 neuropathic pain models in rats and examined its supraspinal mechanism of action.