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1.
J Pineal Res ; 76(1): e12926, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38146602

ABSTRACT

Melatonin is a small natural compound, so called a neuro-hormone that is synthesized mainly in pineal gland in animals. Its main role is to master the clock of the body, under the surveillance of light. In other words, it transfers the information concerning night and day to the peripheral organs which, without it, could not "know" which part of the circadian rhythm the body is in. Besides its main circadian and circannual rhythms mastering, melatonin is reported to be a radical scavenger and/or an antioxidant. Because radical scavengers are chemical species able to neutralize highly reactive and toxic species such as reactive oxygen species, one would like to transfer this property to living system, despite impossibilities already largely reported in the literature. In the present commentary, we refresh the memory of the readers with this notion of radical scavenger, and review the possible evidence that melatonin could be an in vivo radical scavenger, while we only marginally discuss here the fact that melatonin is a molecular antioxidant, a feature that merits a review on its own. We conclude four things: (i) the evidence that melatonin is a scavenger in acellular systems is overwhelming and could not be doubted; (ii) the transposition of this property in living (animal) systems is (a) theoretically impossible and (b) not proven in any system reported in the literature where most of the time, the delay of the action of melatonin is over several hours, thus signing a probable induction of cellular enzymatic antioxidant defenses; (iii) this last fact needs a confirmation through the discovery of a nuclear factor-a key relay in induction processes-that binds melatonin and is activated by it and (iv) we also gather the very important description of the radical scavenging capacity of melatonin in acellular systems that is now proven and shared by many other double bond-bearing molecules. We finally discussed briefly on the reason-scientific or else-that led this description, and the consequences of this claim, in research, in physiology, in pathology, but most disturbingly in therapeutics where a vast amount of money, hope, and patient bien-être are at stake.


Subject(s)
Melatonin , Pineal Gland , Animals , Humans , Melatonin/metabolism , Antioxidants/pharmacology , Antioxidants/metabolism , Pineal Gland/metabolism , Circadian Rhythm/physiology , Reactive Oxygen Species/metabolism
2.
Methods Mol Biol ; 2550: 151-162, 2022.
Article in English | MEDLINE | ID: mdl-36180688

ABSTRACT

Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone that possesses a wide range of biological effects. Most of the main recognized effects of this hormone in mammals are due to its interaction with two G protein-coupled receptors, MT1 and MT2. Ligand-binding studies have been based on the use of its radioligand analog, 2[125I]-iodomelatonin, a super agonist discovered in the early 1990s. This compound has been used in most of the binding studies reported in the literature. Nevertheless, more recently other possibilities arose. This chapter is a brief summary of those alternative radioligands and of their benefits one can find in using them.


Subject(s)
Iodine Radioisotopes , Melatonin , 5-Methoxytryptamine , Animals , Ligands , Mammals/metabolism , Melatonin/pharmacology , Receptors, Melatonin
3.
Eur J Med Chem ; 241: 114620, 2022 Nov 05.
Article in English | MEDLINE | ID: mdl-35933788

ABSTRACT

The past fifty years have been marked by the surge of neurodegenerative diseases. Unfortunately, current treatments are only symptomatic. Hence, the search for new and innovative therapeutic targets for curative treatments becomes a major challenge. Among these targets, the adenosine A2A receptor (A2AAR) has been the subject of much research in recent years. In this paper, we report the design, synthesis and pharmacological analysis of quinazoline derivatives as A2AAR antagonists with high ligand efficiency. This class of molecules has been discovered by a virtual screening and bears no structural semblance with reference antagonist ZM-241385. More precisely, we identified a series of 2-aminoquinazoline as promising A2AAR antagonists. Among them, one compound showed a high affinity towards A2AAR (21a, Ki = 20 nM). We crystallized this ligand in complex with A2AAR, confirming one of our predicted docking poses and opening up possibilities for further optimization to derive selective ligands for specific adenosine receptor subtypes.


Subject(s)
Adenosine A2 Receptor Antagonists , Purinergic P1 Receptor Antagonists , Adenosine A2 Receptor Antagonists/chemistry , Adenosine A2 Receptor Antagonists/pharmacology , Ligands , Molecular Docking Simulation , Purinergic P1 Receptor Antagonists/pharmacology , Quinazolines/pharmacology , Receptor, Adenosine A2A/chemistry , Structure-Activity Relationship
4.
ACS Chem Neurosci ; 13(9): 1382-1394, 2022 05 04.
Article in English | MEDLINE | ID: mdl-35420022

ABSTRACT

Melatonin is a neurohormone that modulates several physiological functions in mammals through the activation of melatonin receptor type 1 and 2 (MT1 and MT2). 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 in vivo imaging of both MT1 and MT2 by positron emission tomography (PET). We identified four previously reported MT ligands with picomolar affinities to the target based on different scaffolds which were also amenable for radiolabeling with either carbon-11 or fluorine-18. [11C]UCM765, [11C]UCM1014, [18F]3-fluoroagomelatine ([18F]3FAGM), and [18F]fluoroacetamidoagomelatine ([18F]FAAGM) have been synthesized in high radiochemical purity and evaluated in wild-type rats. All four tracers showed moderate to high brain permeability in rats with maximum standardized uptake values (SUVmax of 2.53, 1.75, 3.25, and 4.47, respectively) achieved 1-2 min after tracer administration, followed by a rapid washout from the brain. Several melatonin ligands failed to block the binding of any of the PET tracer candidates, while in some cases, homologous blocking surprisingly resulted in increased brain retention. Two 18F-labeled agomelatine derivatives were brought forward to PET scans in non-human primates and autoradiography on human brain tissues. No specific binding has been detected in blocking studies. To further investigate pharmacokinetic properties of the putative tracers, microsomal stability, plasma protein binding, log D, and membrane bidirectional permeability assays have been conducted. Based on the results, we conclude that the fast first pass metabolism by the enzymes in liver microsomes is the likely reason of the failure of our PET tracer candidates. Nevertheless, we showed that PET imaging can serve as a valuable tool to investigate the brain permeability of new therapeutic compounds targeting the melatonergic system.


Subject(s)
Melatonin , Animals , Brain/diagnostic imaging , Brain/metabolism , Fluorine Radioisotopes/metabolism , Ligands , Mammals/metabolism , Melatonin/metabolism , Positron-Emission Tomography/methods , Radiopharmaceuticals , Rats , Receptors, Melatonin/metabolism
5.
ChemMedChem ; 17(3): e202100658, 2022 02 04.
Article in English | MEDLINE | ID: mdl-34797951

ABSTRACT

In our constant search for new successors of agomelatine, we report herein a new series of compounds resulting from bioisosteric modulation of the naphthalene ring. The isoquinoline and tetrahydroisoquinoline derivatives were synthesized and pharmacologically evaluated. This isosteric replacement of the naphthalene group of agomelatine has led to potent agonist and partial agonist compounds with nanomolar melatonergic binding affinities. Overall, the presence of a nitrogen atom was accompanied with a decrease in the binding affinity toward both MT1 and MT2 and the loss of 5HT2C response, especially for tetrahydroisoquinoline in comparison with the parent compound. Interestingly, due to the presence of this nitrogen atom, a notable improvement in the pharmacokinetic properties was observed for all compounds.


Subject(s)
Isoquinolines/pharmacology , Receptors, Melatonin/agonists , Animals , Cells, Cultured , Cricetulus , Dose-Response Relationship, Drug , Humans , Isoquinolines/chemistry , Isoquinolines/metabolism , Ligands , Molecular Docking Simulation , Molecular Structure , Structure-Activity Relationship
6.
J Pharmacol Exp Ther ; 2021 Oct 27.
Article in English | MEDLINE | ID: mdl-34706966

ABSTRACT

In mammals, MT1 and MT2 melatonin receptors are high affinity G protein-coupled receptors and are thought to be involved in the integration of the melatonin signaling throughout the brain and periphery. In the present study, we describe a new melatonin binding site, named MTx, with a peculiar pharmacological profile. This site had a low affinity for 2-[125I]-melatonin in saturation assays in hypothalamus and retina (pKD = 9.13 {plus minus} 0.05, Bmax = 1.12 {plus minus} 0.11 fmol/mg protein and pKD = 8.81 {plus minus} 0.50, Bmax = 7.65 {plus minus} 2.64 fmol/mg protein, respectively) and a very high affinity, in competition assays, for melatonin (pKi = 13.08 {plus minus} 0.18), and other endogenous compounds. Using autoradiography, we showed a preferential localization of the MTx in periventricular areas of the sheep brain, with a density 3 to 8 times higher than those observed for ovine MT1 In addition, using a set of well-characterized ligands, we showed that this site did not correspond to any of the following receptors: MT1, MT2, MT3 , D1, D2, noradrenergic, nor 5-HT2 Based on its affinity for melatonin, MTx did not seem to be implicated in the integration of cerebral melatonin concentration variations since they were saturating for MTx. Nevertheless, it remained of prime importance because of its periventricular distribution, in close contact with the CSF, and its peculiar pharmacological profile responding to both melatoninergic and serotoninergic compounds. Significance Statement Herein a putative new melatonin binding site is described in sheep brain parts in close contact with the 3rd ventricle. The characteristics of the pharmacological profile of this site is different from anything previously reported in the literature. The present work forms the basis of future full pharmacological characterization.

7.
Eur J Med Chem ; 189: 112078, 2020 Mar 01.
Article in English | MEDLINE | ID: mdl-32004937

ABSTRACT

For further development of successors of Agomelatine through modulation of its pharmacokinetic properties, we report herein the design, synthesis and pharmacological results of a new family of melatonin receptor ligands. Issued from the introduction of quinazoline and phthalazine scaffolds carrying an ethyl amide lateral chain and a methoxy group as bioisosteric ligands analogues of previously developed Agomelatine. The biological activity of the prepared analogues was compared with that of Agomelatine. Quinazoline and phthalazine rings proved to be a versatile scaffold for easy feasible MT1 and MT2 ligands. Potent agonists with sub-micromolar binding affinity were obtained. However, the presence of two nitrogen atoms resulted in compounds with lower affinity for both MT1 and MT2, in comparison with the parent compound, balanced by the exhibition of good pharmacokinetic properties.


Subject(s)
Acetamides/chemistry , Phthalazines/chemistry , Quinazolines/chemistry , Receptor, Melatonin, MT1/metabolism , Receptor, Melatonin, MT2/metabolism , Acetamides/metabolism , Animals , CHO Cells , Cricetinae , Cricetulus , HEK293 Cells , Humans , Ligands , Phthalazines/metabolism , Quinazolines/metabolism , Structure-Activity Relationship
8.
J Enzyme Inhib Med Chem ; 34(1): 1321-1346, 2019 Dec.
Article in English | MEDLINE | ID: mdl-31328585

ABSTRACT

For over half a century, the carbazole skeleton has been the key structural motif of many biologically active compounds including natural and synthetic products. Carbazoles have taken an important part in all the existing anti-cancer drugs because of their discovery from a large variety of organisms, including bacteria, fungi, plants, and animals. In this article, we specifically explored the literature from 2012 to 2018 on the anti-tumour activities reported to carbazole derivatives and we have critically collected the most significant data. The most described carbazole anti-tumour agents were classified according to their structure, starting from the tricyclic-carbazole motif to fused tetra-, penta-, hexa- and heptacyclic carbazoles. To date, three derivatives are available on the market and approved in cancer therapy.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Carbazoles/chemistry , Carbazoles/pharmacology , Neoplasms/drug therapy , Animals , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Humans , Molecular Structure , Neoplasms/pathology
9.
10.
Nature ; 569(7755): 289-292, 2019 05.
Article in English | MEDLINE | ID: mdl-31019305

ABSTRACT

The human MT1 and MT2 melatonin receptors1,2 are G-protein-coupled receptors (GPCRs) that help to regulate circadian rhythm and sleep patterns3. Drug development efforts have targeted both receptors for the treatment of insomnia, circadian rhythm and mood disorders, and cancer3, and MT2 has also been implicated in type 2 diabetes4,5. Here we report X-ray free electron laser (XFEL) structures of the human MT2 receptor in complex with the agonists 2-phenylmelatonin (2-PMT) and ramelteon6 at resolutions of 2.8 Å and 3.3 Å, respectively, along with two structures of function-related mutants: H2085.46A (superscripts represent the Ballesteros-Weinstein residue numbering nomenclature7) and N862.50D, obtained in complex with 2-PMT. Comparison of the structures of MT2 with a published structure8 of MT1 reveals that, despite conservation of the orthosteric ligand-binding site residues, there are notable conformational variations as well as differences in [3H]melatonin dissociation kinetics that provide insights into the selectivity between melatonin receptor subtypes. A membrane-buried lateral ligand entry channel is observed in both MT1 and MT2, but in addition the MT2 structures reveal a narrow opening towards the solvent in the extracellular part of the receptor. We provide functional and kinetic data that support a prominent role for intramembrane ligand entry in both receptors, and suggest that there might also be an extracellular entry path in MT2. Our findings contribute to a molecular understanding of melatonin receptor subtype selectivity and ligand access modes, which are essential for the design of highly selective melatonin tool compounds and therapeutic agents.


Subject(s)
Electrons , Lasers , Models, Molecular , Receptor, Melatonin, MT2/chemistry , Receptor, Melatonin, MT2/metabolism , Crystallization , Diabetes Mellitus, Type 2/genetics , Humans , Indenes/chemistry , Indenes/metabolism , Ligands , Melatonin/analogs & derivatives , Melatonin/chemistry , Melatonin/metabolism , Molecular Docking Simulation , Molecular Dynamics Simulation , Mutation , Receptor, Melatonin, MT1/chemistry , Receptor, Melatonin, MT1/metabolism , Receptor, Melatonin, MT2/genetics , Structure-Activity Relationship , Substrate Specificity
11.
Nature ; 569(7755): 284-288, 2019 05.
Article in English | MEDLINE | ID: mdl-31019306

ABSTRACT

Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone that maintains circadian rhythms1 by synchronization to environmental cues and is involved in diverse physiological processes2 such as the regulation of blood pressure and core body temperature, oncogenesis, and immune function3. Melatonin is formed in the pineal gland in a light-regulated manner4 by enzymatic conversion from 5-hydroxytryptamine (5-HT or serotonin), and modulates sleep and wakefulness5 by activating two high-affinity G-protein-coupled receptors, type 1A (MT1) and type 1B (MT2)3,6. Shift work, travel, and ubiquitous artificial lighting can disrupt natural circadian rhythms; as a result, sleep disorders affect a substantial population in modern society and pose a considerable economic burden7. Over-the-counter melatonin is widely used to alleviate jet lag and as a safer alternative to benzodiazepines and other sleeping aids8,9, and is one of the most popular supplements in the United States10. Here, we present high-resolution room-temperature X-ray free electron laser (XFEL) structures of MT1 in complex with four agonists: the insomnia drug ramelteon11, two melatonin analogues, and the mixed melatonin-serotonin antidepressant agomelatine12,13. The structure of MT2 is described in an accompanying paper14. Although the MT1 and 5-HT receptors have similar endogenous ligands, and agomelatine acts on both receptors, the receptors differ markedly in the structure and composition of their ligand pockets; in MT1, access to the ligand pocket is tightly sealed from solvent by extracellular loop 2, leaving only a narrow channel between transmembrane helices IV and V that connects it to the lipid bilayer. The binding site is extremely compact, and ligands interact with MT1 mainly by strong aromatic stacking with Phe179 and auxiliary hydrogen bonds with Asn162 and Gln181. Our structures provide an unexpected example of atypical ligand entry for a non-lipid receptor, lay the molecular foundation of ligand recognition by melatonin receptors, and will facilitate the design of future tool compounds and therapeutic agents, while their comparison to 5-HT receptors yields insights into the evolution and polypharmacology of G-protein-coupled receptors.


Subject(s)
Electrons , Lasers , Models, Molecular , Receptor, Melatonin, MT1/chemistry , Receptor, Melatonin, MT1/metabolism , Acetamides/chemistry , Acetamides/metabolism , Amino Acid Sequence , Antidepressive Agents/chemistry , Antidepressive Agents/metabolism , Crystallization , Humans , Indenes/chemistry , Indenes/metabolism , Ligands , Melatonin/analogs & derivatives , Melatonin/chemistry , Molecular Docking Simulation , Mutation , Receptor, Melatonin, MT1/agonists , Receptor, Melatonin, MT1/genetics , Receptor, Serotonin, 5-HT2C/chemistry , Structure-Activity Relationship , Substrate Specificity
12.
J Enzyme Inhib Med Chem ; 34(1): 224-229, 2019 Dec.
Article in English | MEDLINE | ID: mdl-30734616

ABSTRACT

Using histamine as lead molecule, a library of (hetero)aryl substituted thiazol-2,4-yl derivatives incorporating pyridine as proton shuttling moiety were obtained and investigated as activators of human carbonic anhydrase (CA, EC 4.2.1.1) isoforms I, II, VII and XIV. Some derivatives displayed good activating and selectivity profiles. This study provides an interesting opportunity to study the thiazole scaffold for the design of CA activators (CAAs), possibly acting on the central nervous system and targeting pathologies involving memory and learning impairments.


Subject(s)
Carbonic Anhydrase II/metabolism , Carbonic Anhydrase I/metabolism , Carbonic Anhydrases/metabolism , Enzyme Activators/pharmacology , Thiazoles/pharmacology , Enzyme Activators/chemistry , Humans , Molecular Structure , Thiazoles/chemistry
13.
Bioorg Med Chem ; 26(12): 3296-3307, 2018 07 23.
Article in English | MEDLINE | ID: mdl-29753566

ABSTRACT

Imidazo[1,2a]pyridines have gained much interest in the field of medicinal chemistry research. In the aim of accessing new privileged structure, we decided to design and synthesize 8-aminated-imidazo[1,2a]pyridines substituted on positions 2 and 6. This scaffold, rarely found in the literature, was obtained via palladium-catalyzed coupling reactions (Suzuki reaction or N-hydroxysuccinimidyl activated ester method) and tested on adenosine receptor A2A. We demonstrated how incorporation of an exocyclic amine enhanced affinity towards this receptor while maintaining low cytotoxicity.


Subject(s)
Drug Design , Pyridines/chemistry , Adenosine A2 Receptor Antagonists/chemical synthesis , Adenosine A2 Receptor Antagonists/metabolism , Adenosine A2 Receptor Antagonists/pharmacology , Binding Sites , Catalysis , Cell Line, Tumor , Cell Proliferation/drug effects , HEK293 Cells , Humans , Molecular Docking Simulation , Palladium/chemistry , Protein Structure, Tertiary , Pyridines/metabolism , Pyridines/pharmacology , Receptor, Adenosine A2A/chemistry , Receptor, Adenosine A2A/metabolism , Structure-Activity Relationship
14.
Bioorg Med Chem ; 26(8): 2151-2164, 2018 05 01.
Article in English | MEDLINE | ID: mdl-29559198

ABSTRACT

The chloroquinoline scaffold is characteristic of anti-malarial drugs such as chloroquine (CQ) or amodiaquine (AQ). These drugs are also described for their potential effectiveness against prion disease, HCV, EBV, Ebola virus, cancer, Parkinson or Alzheimer diseases. Amyloid precursor protein (APP) metabolism is deregulated in Alzheimer's disease. Indeed, CQ modifies amyloid precursor protein (APP) metabolism by precluding the release of amyloid-beta peptides (Aß), which accumulate in the brain of Alzheimer patients to form the so-called amyloid plaques. We showed that AQ and analogs have similar effects although having a higher cytotoxicity. Herein, two new series of compounds were synthesized by replacing 7-chloroquinolin-4-amine moiety of AQ by 2-aminomethylaniline and 2-aminomethylphenyle moieties. Their structure activity relationship was based on their ability to modulate APP metabolism, Aß release, and their cytotoxicity similarly to CQ. Two compounds 15a, 16a showed interesting and potent effect on the redirection of APP metabolism toward a decrease of Aß peptide release (in the same range compared to AQ), and a 3-10-fold increased stability of APP carboxy terminal fragments (CTFα and AICD) without obvious cellular toxicity at 100 µM.


Subject(s)
Amyloid beta-Protein Precursor/metabolism , Aniline Compounds/metabolism , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Amodiaquine/chemistry , Amodiaquine/metabolism , Amyloid beta-Peptides/chemistry , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/antagonists & inhibitors , Aniline Compounds/chemistry , Aniline Compounds/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Chloroquine/chemistry , Chloroquine/metabolism , Humans , Protein Binding , Structure-Activity Relationship
15.
Eur J Med Chem ; 144: 151-163, 2018 Jan 20.
Article in English | MEDLINE | ID: mdl-29268131

ABSTRACT

We have recently reported a series of 2-furoyl-benzoxazoles as potential A2A adenosine receptor (A2AR) antagonists. Two hits were identified with interesting pharmacokinetic properties but were find to bind the hA2AR receptor in the micromolar-range. Herein, in order to enhance affinity toward the hA2AR, we explored the C5- and C7-position of hits 1 and 2 based on docking studies. These modifications led to compounds with nanomolar-range affinity (e.g. 6a, Ki = 40 nM) and high antagonist activity (e.g. 6a, IC50 = 70.6 nM). Selected compounds also exhibited interesting in vitro DMPK (Drug Metabolism and Pharmacokinetics) properties including high solubility and low cytotoxicity. Therefore, the benzoxazole ring appears as a highly effective scaffold for the design of new A2A antagonists.


Subject(s)
Adenosine A2 Receptor Antagonists/chemistry , Adenosine A2 Receptor Antagonists/pharmacology , Benzoxazoles/chemistry , Benzoxazoles/pharmacology , Receptor, Adenosine A2A/metabolism , Adenosine A2 Receptor Antagonists/metabolism , Adenosine A2 Receptor Antagonists/pharmacokinetics , Benzoxazoles/metabolism , Benzoxazoles/pharmacokinetics , Caco-2 Cells , Cell Line, Tumor , Drug Design , Humans , Microsomes, Liver/metabolism , Solubility
16.
Medchemcomm ; 8(8): 1659-1667, 2017 Aug 01.
Article in English | MEDLINE | ID: mdl-29250307

ABSTRACT

A pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine antagonist of the A2A adenosine receptor (AR) was functionalized as amine congeners, fluorescent conjugates and a sulfonate, and the A2AAR binding modes were predicted computationally. The optimal n-butyl spacer was incorporated into the following A2AAR-selective (Ki, nM) conjugates: BODIPY630/650 derivative 11 (MRS7396, 24.6) and AlexaFluor488 derivative 12 (MRS7416, 30.3). Flow cytometry of 12 in hA2AAR-expressing HEK-293 cells displayed saturable binding (low nonspecific) and inhibition by known A2AAR antagonists. Water-soluble sulfonate 13 was a highly potent (Ki = 6.2 nM) and selective A2AAR antagonist based on binding and functional assays. Docking and molecular dynamics simulations predicted the regions of interaction of the distal portions of these chain-extended ligands with the A2AAR. The BODIPY630/650 fluorophore of 11 was buried in a hydrophobic interhelical (TM1/TM7) region, while AlexaFluor488 of 12 associated with the hydrophilic extracellular loops. In conclusion, we have identified novel high affinity antagonist probes for A2AAR drug discovery and characterization.

17.
Eur J Med Chem ; 141: 552-566, 2017 Dec 01.
Article in English | MEDLINE | ID: mdl-29102176

ABSTRACT

We recently reported a series of naphthofuranic compounds as constrained agomelatine analogues. Herein, in order to explore alternative ethyl amide side chain rigidification, naphthocyclopentane and quinolinocyclopentane derivatives with various acetamide modulations were synthesized and evaluated at both melatonin (MT1, MT2) and serotonin (5-HT2C) receptors. These modifications has led to compounds with promising dual affinity and high MTs receptors agonist activity. Enantiomeric separation was then performed on selected compounds allowing us to identify levogyre enantiomers (-)-17g and (-)-17k as the highest (MT1, MT2)/5-HT2C dual ligands described nowadays.


Subject(s)
Cyclopentanes/pharmacology , Receptor, Melatonin, MT1/agonists , Receptor, Melatonin, MT2/agonists , Receptor, Serotonin, 5-HT2C/metabolism , Serotonin 5-HT2 Receptor Agonists/pharmacology , Animals , Cell Line , Cricetinae , Cyclopentanes/chemical synthesis , Cyclopentanes/chemistry , Dose-Response Relationship, Drug , Humans , Ligands , Molecular Structure , Serotonin 5-HT2 Receptor Agonists/chemical synthesis , Serotonin 5-HT2 Receptor Agonists/chemistry , Structure-Activity Relationship
18.
J Enzyme Inhib Med Chem ; 32(1): 850-864, 2017 Dec.
Article in English | MEDLINE | ID: mdl-28661196

ABSTRACT

The development of adenosine A2A receptor antagonists has received much interest in recent years for the treatment of neurodegenerative diseases. Based on docking studies, a new series of 2-arylbenzoxazoles has been identified as potential A2AR antagonists. Structure-affinity relationship was investigated in position 2, 5 and 6 of the benzoxazole heterocycle leading to compounds with a micromolar affinity towards the A2A receptor. Compound F1, with an affinity of 1 µm, presented good absorption, distribution, metabolism and excretion properties with an excellent aqueous solubility (184 µm) without being cytotoxic at 100 µm. This compound, along with low-molecular weight compound D1 (Ki = 10 µm), can be easily modulated and thus considered as relevant starting points for further hit-to-lead optimisation.


Subject(s)
Adenosine A2 Receptor Antagonists/pharmacology , Benzoxazoles/pharmacology , Drug Design , Receptor, Adenosine A2A/metabolism , Adenosine A2 Receptor Antagonists/chemical synthesis , Adenosine A2 Receptor Antagonists/chemistry , Benzoxazoles/chemical synthesis , Benzoxazoles/chemistry , Cell Death/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , HEK293 Cells , Humans , Models, Molecular , Molecular Structure , Solubility , Structure-Activity Relationship , Tumor Cells, Cultured
19.
Eur J Med Chem ; 127: 621-631, 2017 Feb 15.
Article in English | MEDLINE | ID: mdl-28131094

ABSTRACT

New series of melatonergic ligands issued from two methoxy-quinolinic scaffolds (2-MQ and 3-MQ), were designed and synthesized. Herein we report the synthetic scheme and pharmacological results of the new prepared compounds. Investigation of compound 11a, the strict 2-MQ analogue, revealed the promising potential of this series. Therefore, pharmacomodulation of the acetamide function of 11a has led to compounds with different pharmacological profiles and the emergence of an MT2 selectivity. Besides, sulphonamide 11b showed the most important MT2 selectivity of this series (167 folds) while methyl and ethyl-ureas 11f and 11g represented the most potent melatonergic ligands of this study.


Subject(s)
Drug Design , Melatonin/metabolism , Quinolines/chemical synthesis , Quinolines/pharmacology , Animals , CHO Cells , Cricetinae , Cricetulus , HEK293 Cells , Humans , Indoles/chemistry , Ligands , Quinolines/chemistry , Structure-Activity Relationship
20.
Eur J Med Chem ; 109: 360-70, 2016 Feb 15.
Article in English | MEDLINE | ID: mdl-26820449

ABSTRACT

Following our research for new melatonergic ligands, herein we report the design, synthesis and biological evaluation of new series of naphthofuranic derivatives as MT1 and MT2 ligands. Binding affinity results of the prepared compounds revealed good binding affinities at both melatonin receptor subtypes. Particularly, compound 6a behaved as an MT1 partial agonist and MT2 full agonist and exhibited an excellent binding affinity at MT2 (Ki = 0.09 nM). In addition, lateral chain displacement from position 1 to 2 of the furan core had no effect on the binding affinity at both MT1 and MT2, while elongation of this side chain, led to decreased melatonergic binding affinities.


Subject(s)
Furans/chemistry , Furans/pharmacology , Naphthalenes/chemistry , Naphthalenes/pharmacology , Receptor, Melatonin, MT1/metabolism , Receptor, Melatonin, MT2/metabolism , Animals , CHO Cells , Cricetulus , Drug Design , HEK293 Cells , Humans , Ligands , Melatonin/analogs & derivatives , Melatonin/metabolism , Receptor, Melatonin, MT1/agonists , Receptor, Melatonin, MT2/agonists
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