Philippe Delagrange

Servier, Suresnes, Île-de-France, France

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Publications (198)756.67 Total impact

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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.
    Journal of Pineal Research 10/2015; DOI:10.1111/jpi.12294 · 9.60 Impact Factor
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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.
    Journal of Medicinal Chemistry 09/2015; 58(18). DOI:10.1021/acs.jmedchem.5b01066 · 5.45 Impact Factor
  • R.M Tordera · P. Delagrange · C. Gabriel · M. Erburu · E. Puerta · E. Beltran ·

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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.
    Journal of Biological Chemistry 03/2015; 290(18). DOI:10.1074/jbc.M114.559542 · 4.57 Impact Factor
  • 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.
    Molecular Psychiatry 01/2015; 20(11). DOI:10.1038/mp.2014.169 · 14.50 Impact Factor
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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.
    European Journal of Medicinal Chemistry 12/2014; 90C:822-833. DOI:10.1016/j.ejmech.2014.12.021 · 3.45 Impact Factor
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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.
    The Journal of Physiology 09/2014; 592(22). DOI:10.1113/jphysiol.2014.280065 · 5.04 Impact Factor
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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).
    Medicinal Chemistry Communication 08/2014; 5(9). DOI:10.1039/C4MD00149D · 2.50 Impact Factor
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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.
    PLoS ONE 06/2014; 9(6):e100616. DOI:10.1371/journal.pone.0100616 · 3.23 Impact Factor
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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.
    British Journal of Pharmacology 04/2014; 171(15). DOI:10.1111/bph.12720 · 4.84 Impact Factor
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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.
    Neuroscience Letters 03/2014; 566. DOI:10.1016/j.neulet.2014.02.044 · 2.03 Impact Factor
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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.
    ACS Medicinal Chemistry Letters 02/2014; 5(2):158-161. DOI:10.1021/ml4004155 · 3.12 Impact Factor
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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.
    Bioorganic & medicinal chemistry 01/2014; 22(3). DOI:10.1016/j.bmc.2013.12.054 · 2.79 Impact Factor
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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.
    British Journal of Pharmacology 01/2014; 171(1). DOI:10.1111/bph.12457 · 4.84 Impact Factor
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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.
    The Journal of Physiology 11/2013; 592(4). DOI:10.1113/jphysiol.2013.263319 · 5.04 Impact Factor
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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.
    ChemMedChem 11/2013; 8(11). DOI:10.1002/cmdc.201300294 · 2.97 Impact Factor
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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.
    International Journal of Molecular Sciences 05/2013; 14(5):8948-8962. DOI:10.3390/ijms14058948 · 2.86 Impact Factor
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    ABSTRACT: Sheep are gregarious mammals with complex social interactions. As such, they are very sensitive to social isolation and constitute a relevant animal model to study specifically the biological consequences of social stress. We examined previously the behavioral and endocrine responses in ewes isolated socially in the familiar conspecific withdrawal model (FCW) and showed that stressful responses increased and maintenance behaviors decreased, confirming that social isolation is a strong stressor in sheep. Melatonin synchronizes seasonal and circadian rhythms; and several studies reported its implication in cognitive processes as emotion. Here we investigated its role in the modulation of social stressful responses. Firstly, we studied ewes in the FCW model during the day (characterized by low melatonin levels) and the night (characterized by high melatonin levels). We found lower stressful responses (significant lower levels of cortisol plasma, number of foot pawings, of circling attempts) during the night as compared to the day. To investigate whether these effects were due to melatonin or to darkness, we submitted ewes to FCW during the night with lights on, a condition that suppresses melatonin secretion. Ewes infused with melatonin under these conditions showed decreased stressful responses (significant lower levels cortisol plasma, number of vocalizations, time spent with the head out of the cage) as compared to ewes infused with saline. These findings demonstrate that melatonin diminishes the endocrine and behavioral impact of social isolation in ewes and support the idea that melatonin has a calming effect in socially stressful situations.
    Psychoneuroendocrinology 01/2013; 38(8). DOI:10.1016/j.psyneuen.2012.12.011 · 4.94 Impact Factor
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    ABSTRACT: Novel conformationally restricted analogues of agomelatine were synthesized and pharmacologically evaluated at MT(1) and MT(2) melatoninergic receptors. Replacement of the N-acetyl side chain of agomelatine by oxathiadiazole-2-oxide (compound 3), oxadiazole-5(4H)-one (compound 4), tetrazole (compound 5), oxazolidinone (compound 7a), pyrrolidinone (compound 7b), imidazolidinedione (compound 12), thiazole (compounds 13 and 14) and isoxazole moieties (compound 15) led to a decrease of the melatoninergic binding affinities, particularly at MT(1). Compounds 7a and 7b exhibiting nanomolar affinity towards the MT(2) receptors subtypes have shown the most interesting pharmacological results of this series with the appearance of a weak MT(2)-selectivity.
    Molecules 12/2012; 18(1):154-66. DOI:10.3390/molecules18010154 · 2.42 Impact Factor
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    ABSTRACT: Ever since the idea arose that melatonin might promote sleep and resynchronize circadian rhythms, many research groups have centered their efforts on obtaining new melatonin receptor ligands whose pharmacophores include an aliphatic chain of variable length united to an N-alkylamide and a methoxy group (or a bioisostere), linked to a central ring. Substitution of the indole ring found in melatonin with a naphthalene or quinoline ring leads to compounds of similar affinity. The next step in this structural approximation is to introduce a quinoxaline ring (a bioisostere of the quinoline and naphthalene rings) as the central nucleus of future melatoninergic ligands.
    Molecules 12/2012; 17(7):7737-57. DOI:10.3390/molecules17077737 · 2.42 Impact Factor

Publication Stats

5k Citations
756.67 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