Philippe Delagrange

Servier, Suresnes, Île-de-France, France

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Publications (202)770.52 Total impact

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    ABSTRACT: Melatonin exerts a variety of physiological activities that are mainly relayed through the MT1 and MT2 receptors. Low expressions of these receptors in tissues have led to widespread experimental use of the agonist 2-[125I]-iodomelatonin as a substitute for melatonin. We described three iodinated ligands: DIV880 & S70254 that are specific ligands at MT2 receptors, and SD6, an analogue of 2-[125I]-iodomelatonin with slightly different characteristics. Here we further characterized these new ligands, with regards to their molecular pharmacology. We performed binding experiments, saturation assays, association/dissociation rate measurements and autoradiography using sheep and rat tissues and recombinant cell lines. Our results showed that [125I]-S 70254 is selective for the MT2 receptor, and can be used with both cells and tissue. This radioligand can be used in autoradiography. Similarly, DIV880, a partial agonist (43% of melatonin on GTPγS binding assay) selective of MT2, can be used as a tool to selectively describe the pharmacology of this receptor in tissues samples. The molecular pharmacology of both hMT1 and hMT2, using a series of 24 ligands at these receptors and the new radioligands did not lead to noticeable variations in the profiles. For the first time, we described radiolabelled tools that are specific for one of the melatonin receptors (MT2). These tools are amenable to binding experiments and to autoradiography using sheep or rat tissues. These specific tools will permit to better understand the role and implication in physio-pathological processes of the melatonin receptors.
    Full-text · Article · Jan 2016 · Journal of Pharmacology and Experimental Therapeutics
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    ABSTRACT: We report herein an efficient synthesis of 2-substituted furo[3,2-b]pyridines and their biological evaluation as melatonin receptors ligands. The proposed eight-step sequence ending with a Suzuki coupling allowed a rapid access to various analogues. The steric hindrance and the conformation of the aryl group in C2-position were evaluated regarding the selectivity of the molecule for one of the two high affinity melatonin receptors as well as the activity profile of the compound. Introduction of 1-naphthyl substituent gave the best result in terms of selectivity with a MT1/MT2 ratio of about 150 (MT1 Ki = 198 nM, MT2 Ki = 1.3 nM).
    No preview · Article · Jan 2016 · European Journal of Medicinal Chemistry
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    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.
    Full-text · Article · Dec 2015 · European Journal of Medicinal Chemistry
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    ABSTRACT: In mammals, the hormone melatonin is mainly produced by the pineal gland with nocturnal peak levels. Its peripheral and central actions rely either on its intrinsic antioxidant properties or on binding to melatonin MT1 and MT2 receptors, belonging to the G protein-coupled receptor (GPCR) super-family. Melatonin has been reported to be involved in many functions of the central nervous system such as circadian rhythm regulation, neurotransmission, synaptic plasticity, memory, sleep and also in Alzheimer's disease and depression. However, little is known about the subcellular localization of melatonin receptors and the molecular aspects involved in neuronal functions of melatonin. Identification of protein complexes associated with GPCRs has been shown to be a valid approach to improve our understanding of their function. By combining proteomic and genomic approaches we built an interactome of MT1 and MT2 receptors, which comprises 378 individual proteins. Among the proteins interacting with MT1 , but not with MT2 , we identified several presynaptic proteins, suggesting a potential role of MT1 in neurotransmission. Presynaptic localization of MT1 receptors in the hypothalamus, striatum and cortex was confirmed by subcellular fractionation experiments and immunofluoresence microscopy. MT1 physically interacts with the voltage-gated calcium channel Cav 2.2 and inhibits Cav 2.2-promoted Ca(2+) entry in an agonist-independent manner. In conclusion, we show that MT1 is part of the presynaptic protein network and negatively regulates Cav 2.2 activity, providing a first hint for potential synaptic functions of MT1 . This article is protected by copyright. All rights reserved.
    Full-text · Article · Oct 2015 · Journal of Pineal Research
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    ABSTRACT: 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. The compounds were tested for binding affinity and intrinsic activity at human MT1 and MT2 receptors. Structural optimization resulted in N-[(1-benzyl-1,2,3,4-tetrahydro-5-methoxyquinolin-2-yl)methyl]propionamide (UCM1014), with picomolar MT2 binding affinity (Ki = 0.001 nM), more than 10,000-fold selectivity over the MT1 receptor and a full agonist profile (GTPγS test), being the most potent MT2-selective full agonist reported to date. Molecular dynamics simulations provided a rationale for high binding affinity, stereoselectivity and agonist behavior of these novel melatonin receptor ligands, based on superposition models and conformational preference.
    No preview · Article · Sep 2015 · Journal of Medicinal Chemistry
  • R.M Tordera · P. Delagrange · C. Gabriel · M. Erburu · E. Puerta · E. Beltran

    No preview · Article · Sep 2015
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    ABSTRACT: Inasmuch as the neurohormone melatonin is synthetically derived from serotonin (5-HT), a close interrelationship between both has long been suspected. The present study reveals a hitherto-unrecognized crosstalk mediated via physical association of melatonin MT2 and 5-HT2C receptors into functional heteromers. This is of particular interest in light of the "synergistic" melatonin agonist/5-HT2C antagonist profile of the novel antidepressant, agomelatine. A suite of co-immunoprecipitation, BRET and pharmacological techniques was exploited to demonstrate formation of functional MT2 and 5-HT2C receptor heteromers both in transfected cells and in human cortex and hippocampus. MT2/5-HT2C heteromers amplified the 5-HT-mediated Gq/PLC response and triggered melatonin-induced unidirectional trans-activation of the 5-HT2C protomer of MT2/5-HT2C heteromers. Pharmacological studies revealed distinct functional properties for agomelatine, which shows "biased signaling". These observations demonstrate the existence of functionally-unique MT2/5-HT2C heteromers, and suggest that the antidepressant agomelatine has a distinctive profile at these sites potentially involved in its therapeutic effects on major depression and generalized anxiety disorder. Finally, MT2/5-HT2C heteromers provide a new strategy for the discovery of novel agents for the treatment of psychiatric disorders. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    No preview · Article · Mar 2015 · Journal of Biological Chemistry
  • B P Godsil · B Bontempi · F Mailliet · P Delagrange · M Spedding · T M Jay
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    ABSTRACT: Antidepressant drugs are commonly prescribed treatments for anxiety disorders, and there is growing interest in understanding how these drugs impact fear extinction because extinction learning is pivotal to successful exposure-based therapy (EBT). A key objective within this domain is understanding how antidepressants alter the activation of specific elements of the limbic-based network that governs such fear processing. Chronic treatment with the antidepressant tianeptine has been shown to reduce the acquisition of extinction learning in rats, yet the drug's acute influence on activation in prefrontal and amygdalar regions, and on extinction learning are not well understood. To assess its influence on cellular activation, rats were injected with tianeptine and Fos immunoreactivity was measured in these regions. Acute tianeptine treatment selectively altered Fos expression within subdivisions of the central nucleus of the amygdala (CEA) in a bidirectional manner that varied in relation to ongoing activation within the capsular subdivision and its prefrontal and intra-amygdalar inputs. This pattern of results suggests that the drug can conditionally modulate the activation of CEA subdivisions, which contain microcircuits strongly implicated in fear processing. The effect of acute tianeptine was also examined with respect to the acquisition, consolidation and expression of fear extinction in rats. Acute tianeptine attenuated extinction learning as well as the recall of extinction memory, which underscores that acute dosing with the drug could alter learning during EBT. Together these findings provide a new perspective for understanding the mechanism supporting tianeptine's clinical efficacy, as well as its potential influence on CEA-based learning mechanisms.Molecular Psychiatry advance online publication, 6 January 2015; doi:10.1038/mp.2014.169.
    No preview · Article · Jan 2015 · Molecular Psychiatry
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    ABSTRACT: In this paper we report the investigation of C-3 and β-acetamide positions of agomelatine analogues. Concomitant insertion of a hydroxymethyl in the β-acetamide position and aliphatic groups in C-3 position produced a positive effect on both melatonin (MT1, MT2) and serotonin (5-HT2C) binding affinities. In particular, the allyl 6b and ethyl 15a represented the more interesting compounds of this series. Furthermore, the introduction of methyl cycloalkyl groups (compounds 11a, 12a) exhibited no change in both MT2 and 5-HT2C binding affinities while a decrease of MT1 binding affinity occurred leading to an MT2 selectivity. Finally, the acetamide modulation has led to methyl thiourea 11h, with a weak MT2 selectivity. Copyright © 2014. Published by Elsevier Masson SAS.
    Full-text · Article · Dec 2014 · European Journal of Medicinal Chemistry
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    ABSTRACT: Light input from the retina acts on clock neurones in the suprachiasmatic nuclei (SCN) and the intrinsic daily electrical output of these cell autonomous clocks coordinates circadian rhythms in the brain and body.Cells in the lateral habenula express clock genes and anatomical studies indicate that SCN output and retinal pathways terminate in this structure.Using a brain slice preparation isolating the lateral habenula from retinal and SCN inputs, we found mouse lateral habenula neurones exhibit a daily variation in their electrical properties that is dependent on a functional molecular clock.Prokineticin 2, a putative output signal of the SCN, changed lateral habenula neuronal activity through enhancing inhibitory signalling. In response to retinal illumination in vivo, lateral habenula neurones sluggishly altered their electrical activity.These studies indicate that mouse lateral habenula neurones possess intrinsic timekeeping capabilities and show for the first time that they are responsive to extrinsic SCN and retinal signals.
    No preview · Article · Sep 2014 · The Journal of Physiology
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    ABSTRACT: We report herein the racemic resolution and pharmacological evaluation of naphthalenic ligand analogues of compound 3a. Propionamide 3b and fluoroacetamide 3c showed a good pharmacological profile towards MT1, MT2 and 5-HT2C. Hence, their enantiomers were successfully separated from racemates (±)-3a and (±)-3b and evaluated for their binding affinities and antidepressant activity. Binding results revealed that (−)-R-enantiomers were more potent than (+)-S-enantiomers. Furthermore, the (−)-R-enantiomers exhibited high binding affinities with partial agonist activity at melatonin MT1 and MT2 receptor subtypes and antagonist activity at the serotonin 5-HT2C receptor subtype. The R-fluoroacetamide 3c demonstrated the most potent binding affinity towards the 5-HT2C receptor subtype (pKi = 6.73 ± 0.02).
    Full-text · Article · Aug 2014 · Medicinal Chemistry Communication
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    ABSTRACT: The human melatonin MT1 receptor-belonging to the large family of G protein-coupled receptors (GPCRs)-plays a key role in circadian rhythm regulation and is notably involved in sleep disorders and depression. Structural and functional information at the molecular level are highly desired for fine characterization of this receptor; however, adequate techniques for isolating soluble MT1 material suitable for biochemical and biophysical studies remain lacking. Here we describe the evaluation of a panel of constructs and host systems for the production of recombinant human MT1 receptors, and the screening of different conditions for their solubilization and purification. Our findings resulted in the establishment of an original strategy using a mixture of Fos14 and CHAPS detergents to extract and purify a recombinant human MT1 from Pichia pastoris membranes. This procedure enabled the recovery of relatively pure, monomeric and ligand-binding active MT1 receptor in the near-milligram range. A comparative study based on extensive ligand-binding characterization highlighted a very close correlation between the pharmacological profiles of MT1 purified from yeast and the same receptor present in mammalian cell membranes. The high quality of the purified MT1 was further confirmed by its ability to activate its cognate Gαi protein partner when reconstituted in lipid discs, thus opening novel paths to investigate this receptor by biochemical and biophysical approaches.
    Full-text · Article · Jun 2014 · PLoS ONE
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    ABSTRACT: Agomelatine behaves both as a potent agonist at melatonergic MT1 and MT2 receptors and as a neutral antagonist at 5-HT2C receptors. Accumulating evidence in a broad range of experimental procedures supports the notion that the psychotropic effects of agomelatine are due to the synergy between its melatonergic- and serotonergic effects. The recent demonstration of the existence of heteromeric complexes of MT1 and MT2 with 5-HT2C receptors at the cellular level may explain how these two properties of agomelatine translate into a synergistic action that, for example, leads to increases in proliferation, maturation and survival through modulation of multiple cellular pathways (increase in trophic factors, synaptic remodeling glutamate signaling) and key targets (early genes, kinases).The present review focuses on the pharmacological properties of this novel antidepressant. Its mechanism of action, strikingly different from that of conventional classes of antidepressants, opens perspectives toward a better understanding of the physiopathological bases underlying depression.
    No preview · Article · Apr 2014 · British Journal of Pharmacology
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    ABSTRACT: Short duration immobilization stress (IS) in younger rats is followed by a sleep rebound involving slow wave sleep (SWS) and, more particularly, rapid eye movement (REM) sleep. This rebound, expressing the ability of the brain to confront a stress challenge, is now accepted as a marker of the homeostasis. In older rats (24-25 months), however, an IS of 1h is not followed by a sleep rebound. To determine whether this impairment is reversible, we analyzed the effects of the antidepressant agomelatine, on stress-related sleep rebound in older animals. Older and younger (3-5 months) rats were equipped with electroencephalographic (EEG) and electromyographic (EMG) electrodes and polygraphic recordings were achieved under basal conditions with a digitized set-up. Older rats were pretreated with agomelatine (40mg/kg/day) for 3 days, with IS applied on the third day, whereas younger rats were only subjected to IS. Polygraphic recordings achieved under basal conditions confirmed the conventional impairments of the sleep/wake architecture in older animals, including decreased delta power, shortened REM sleep bouts, and modified sleep/wake circadian rhythms. Older rats pretreated with agomelatine for 3 days showed a reversal of the deficit observed in the beta-1, but not in the delta, EEG power band. Application of an IS to older rats after agomelatine pretreatment resulted in a REM sleep rebound in response to stress. These findings indicate that agomelatine, by improving beta-1 EEG power band and by inducing stress-related sleep rebound in older animals, contributes to the homeostasis maintenance.
    Full-text · Article · Mar 2014 · Neuroscience Letters
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    ABSTRACT: An original design and synthesis of fluorescent ligands for melatonin receptor studies is presented and consists in the fusion of the endogenous ligand with the fluorescent BODIPY core. Probes I-IV show high affinities for MT1 and MT2 melatonin receptors and exhibit fluorescence properties compatible with cell observation.
    No preview · Article · Feb 2014 · ACS Medicinal Chemistry Letters
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    ABSTRACT: Herein we describe the synthesis of novel tricyclic analogues issued from the rigidification of the methoxy group of the benzofuranic analogue of melatonin as MT1 and MT2 ligands. Most of the synthesized compounds displayed high binding affinities at MT1 and MT2 receptors subtypes. Compound 6b (MT1, Ki=0.07nM; MT2, Ki=0.08nM) exhibited with the vinyl 6c and allyl 6d the most interesting derivatives of this series. Functional activity of these compounds showed full agonist activity with EC50 in the nanomolar range. Compounds 6a (EC50=0.8nM and Emax=98%) and 6b (EC50=0.2nM and Emax=121%) exhibited good pharmacological profiles.
    Full-text · Article · Jan 2014 · Bioorganic & medicinal chemistry
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    ABSTRACT: Background and purpose: Melatonin receptors have been extensively characterized regarding their affinity and pharmacology, mostly using 2-[(125)I]-melatonin as a radioligand. Although [(3)H]-melatonin has the advantage of corresponding to the endogenous ligand of the receptor, its binding has not been well described. Experimental approach: We characterized [(3)H]-melatonin binding to the hMT₁ and hMT₂ receptors expressed in a range of cell lines and obtained new insights into the molecular pharmacology of melatonin receptors. Key results: The binding of [(3)H]-melatonin to the hMT₁ and hMT₂ receptors displayed two sites on the saturation curves. These two binding sites were observed on cell membranes expressing recombinant receptors from various species as well as on whole cells. Furthermore, our GTPγS/NaCl results suggest that these sites on the saturation curves correspond to the G-protein coupled and uncoupled states of the receptors, whose pharmacology was extensively characterized. Conclusions and implications: hMT₁ and hMT₂ receptors spontaneously exist in two states when expressed in cell lines; these states can be probed by [(3)H]-melatonin binding. Overall, our results suggest that physiological regulation of the melatonin receptors may result from complex and subtle mechanisms, a small difference in affinity between the active and inactive states of the receptor, and spontaneous coupling to G-proteins.
    Full-text · Article · Jan 2014 · British Journal of Pharmacology
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    Kanwal Sakhi · Mino D C Belle · Nicole Gossan · Philippe Delagrange · Hugh D Piggins
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    ABSTRACT: Neurones of the suprachiasmatic nucleus (SCN) contain a molecular clock that drives these cells to exhibit daily rhythms in electrical activity.The molecular clock may also be present in another brain structure, the medial habenula, and here we tested whether medial habenula neurones show daily changes in their electrical activity.Using a brain slice preparation in which the medial habenula is isolated from inputs from the SCN, we made recordings from mouse medial habenula neurones and determined that they exhibit daily variation in their electrical properties.By contrast, in mice lacking functional molecular clocks, medial habenula neurones did not show overt daily change in their electrical activity.These studies indicate for the first time that medial habenula neurones exhibit daily changes in electrical activity that require a functional molecular clock, but do not depend on signals from the SCN.
    Full-text · Article · Nov 2013 · The Journal of Physiology
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    ABSTRACT: Agomelatine is a naphthalenic analogue of melatonin that is in clinical use for the treatment of major depressive disorders. Interestingly, while agomelatine exhibits potent affinity for melatonin receptors, it binds with only moderate affinity to the serotonin 5-HT2C receptor. Optimization of agomelatine toward this target could further potentiate its clinical efficacy. To explore this hypothesis and to access derivatives in which a key point of agomelatine metabolism is blocked, a series of naphthalenic derivatives was designed and synthesized as novel analogues of agomelatine. Most of the prepared compounds exhibited good binding affinity at the melatonin MT1 and MT2 receptor subtypes. Two compounds, an acetamide and an acrylamide derivative, exhibited good binding affinities at both the human melatonin (MT) receptors and the serotonin 5-HT2C receptor subtype, with pKi values of 7.96 and 7.95 against MT1 , 7.86 and 8.68 against MT2, and 6.64 and 6.44 against 5-HT2C , respectively.
    Full-text · Article · Nov 2013 · ChemMedChem
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    ABSTRACT: Melatonin receptors have been studied for several decades. The low expression of the receptors in tissues led the scientific community to find a substitute for the natural hormone melatonin, the agonist 2-[125I]-iodomelatonin. Using the agonist, several hundreds of studies were conducted, including the discovery of agonists and antagonists for the receptors and minute details about their molecular behavior. Recently, we attempted to expand the panel of radioligands available for studying the melatonin receptors by using the newly discovered compounds SD6, DIV880, and S70254. These compounds were characterized for their affinities to the hMT1 and hMT2 recombinant receptors and their functionality in the classical GTPS system. SD6 is a full agonist, equilibrated between the receptor isoforms, whereas S70254 and DIV880 are only partial MT2 agonists, with Ki in the low nanomolar range while they have no affinity to MT1 receptors. These new tools will hopefully allow for additions to the current body of information on the native localization of the receptor isoforms in tissues.
    Full-text · Article · May 2013 · International Journal of Molecular Sciences

Publication Stats

6k Citations
770.52 Total Impact Points


  • 2015
    • Servier
      Suresnes, Île-de-France, France
  • 2006-2012
    • Institut de France
      Lutetia Parisorum, Île-de-France, France
  • 2011
    • Innovative Drug Research Solutions
      Bhaganagar, Telangana, India
  • 2010
    • Servier Laboratories
      Neuilly, Île-de-France, France
    • Université de Caen Basse-Normandie
      • Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN)
      Caen, Lower Normandy, France
  • 2005
    • University of Wollongong
      • School of Chemistry
      City of Greater Wollongong, New South Wales, Australia
  • 1997-2005
    • Iris Pharma
      Provence-Alpes-Côte d'Azur, France
  • 2003
    • Institut Louis Bachelier
      Lutetia Parisorum, Île-de-France, France
  • 2000
    • Université Paris-Sud 11
      • Faculty of Pharmaceutical Sciences
      Orsay, Île-de-France, France