Dubocovich M.L.,State University of New York at Buffalo |
Dubocovich M.L.,Northwestern University |
Delagrange P.,Institute Of Recherches Servier |
Krause D.N.,University of California at Irvine |
And 3 more authors.
Pharmacological Reviews | Year: 2010
The hormone melatonin (5-methoxy-N-acetyltryptamine) is synthesized primarily in the pineal gland and retina, and in several peripheral tissues and organs. In the circulation, the concentration of melatonin follows a circadian rhythm, with high levels at night providing timing cues to target tissues endowed with melatonin receptors. Melatonin receptors receive and translate melatonin's message to influence daily and seasonal rhythms of physiology and behavior. The melatonin message is translated through activation of two G protein-coupled receptors, MT1 and MT2, that are potential therapeutic targets in disorders ranging from insomnia and circadian sleep disorders to depression, cardiovascular diseases, and cancer. This review summarizes the steps taken since melatonin's discovery by Aaron Lerner in 1958 to functionally characterize, clone, and localize receptors in mammalian tissues. The pharmacological and molecular properties of the receptors are described as well as current efforts to discover and develop ligands for treatment of a number of illnesses, including sleep disorders, depression, and cancer. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics.
Edwards G.,University of Manchester |
Feletou M.,Institute Of Recherches Servier |
Weston A.H.,University of Manchester
Pflugers Archiv European Journal of Physiology | Year: 2010
The term endothelium-derived hyperpolarising factor (EDHF) was introduced in 1987 to describe the hypothetical factor responsible for myocyte hyperpolarisations not associated with nitric oxide (EDRF) or prostacyclin. Two broad categories of EDHF response exist. The classical EDHF pathway is blocked by apamin plus TRAM-34 but not by apamin plus iberiotoxin and is associated with endothelial cell hyperpolarisation. This follows an increase in intracellular [Ca 2+] and the opening of endothelial SK Ca and IK Ca channels preferentially located in caveolae and in endothelial cell projections through the internal elastic lamina, respectively. In some vessels, endothelial hyperpolarisations are transmitted to myocytes through myoendothelial gap junctions without involving any EDHF. In others, the K + that effluxes through SK Ca activates myocytic and endothelial Ba 2+-sensitive K IR channels leading to myocyte hyperpolarisation. K + effluxing through IK Ca activates ouabain-sensitive Na +/K +- ATPases generating further myocyte hyperpolarisation. For the classical pathway, the hyperpolarising "factor" involved is the K + that effluxes through endothelial K Ca channels. During vessel contraction, K + efflux through activated myocyte BK Ca channels generates intravascular K + clouds. These compromise activation of Na +/K +- ATPases and K IR channels by endothelium-derived K + and increase the importance of gap junctional electrical coupling in myocyte hyperpolarisations. The second category of EDHF pathway does not require endothelial hyperpolarisation. It involves the endothelial release of factors that include NO, HNO, H 2O 2 and vasoactive peptides as well as prostacyclin and epoxyeicosatrienoic acids. These hyperpolarise myocytes by opening various populations of myocyte potassium channels, but predominantly BK Ca and/or K ATP, which are sensitive to blockade by iberiotoxin or glibenclamide, respectively. © Springer-Verlag 2009.
Watson D.J.G.,University of Nottingham |
Loiseau F.,Institute Of Recherches Servier |
Ingallinesi M.,Institute Of Recherches Servier |
Millan M.J.,Institute Of Recherches Servier |
And 2 more authors.
Neuropsychopharmacology | Year: 2012
Dopamine D 3 receptor antagonists exert pro-cognitive effects in both rodents and primates. Accordingly, this study compared the roles of dopamine D 3 vs D 2 receptors in social novelty discrimination (SND), which relies on olfactory cues, and novel object recognition (NOR), a visual-recognition task. The dopamine D 3 receptor antagonist, S33084 (0.04-0.63 mg/kg), caused a dose-related reversal of delay-dependent impairment in both SND and NOR procedures in adult rats. Furthermore, mice genetically deficient in dopamine D 3 receptors displayed enhanced discrimination in the SND task compared with wild-type controls. In contrast, acute treatment with the preferential dopamine D 2 receptor antagonist, L741,626 (0.16-5.0 mg/kg), or with the dopamine D 3 agonist, PD128,907 (0.63-40 μg/kg), caused a dose-related impairment in performance in rats in both tasks after a short inter-trial delay. Bilateral microinjection of S33084 (2.5 μg/side) into the prefrontal cortex (PFC) of rats increased SND and caused a dose-related (0.63-2.5 μg/side) improvement in NOR, while intra-striatal injection (2.5 μg/side) had no effect on either. In contrast, bilateral microinjection of L741,626 into the PFC (but not striatum) caused a dose-related (0.63-2.5 μg/side) impairment of NOR. These observations suggest that blockade of dopamine D 3 receptors enhances both SND and NOR, whereas D 3 receptor activation or antagonism of dopamine D 2 receptor impairs cognition in these paradigms. Furthermore, these actions are mediated, at least partly, by the PFC. These data have important implications for exploitation of dopaminergic mechanisms in the treatment of schizophrenia and other CNS disorders, and support the potential therapeutic utility of dopamine D 3 receptor antagonism. © 2012 American College of Neuropsychopharmacology. All rights reserved.
Watson D.J.G.,University of Nottingham |
Marsden C.A.,University of Nottingham |
Millan M.J.,Institute Of Recherches Servier |
Fone K.C.F.,University of Nottingham
International Journal of Neuropsychopharmacology | Year: 2012
Dopamine D3 receptors are densely expressed in mesolimbic projection areas, and selective antagonists enhance cognition, consistent with their potential therapeutic use in the treatment of schizophrenia. This study examines the effect of dopamine D3vs. D2 receptor antagonists on the cognitive impairment and hyperactivity produced by social isolation of rat pups, in a neurodevelopmental model of certain deficits of schizophrenia. Three separate groups of male Lister hooded rats were group-housed or isolation-reared from weaning. Six weeks later rats received either vehicle or the dopamine D3 selective antagonist, S33084 (0.04 and 0.16 mg/kg), the preferential D3 antagonist, S33138 (0.16 and 0.63 mg/kg) or the preferential D2 antagonist, L-741,626 (0.63 mg/kg) s.c. 30 min prior to recording; horizontal locomotor activity in a novel arena for 60 min and, the following day, novel object discrimination using a 2-h inter-trial interval. Isolation rearing induced locomotor hyperactivity in a novel arena and impaired novel object discrimination compared to that in group-housed littermates. Both S33084 and S33138 restored novel object discrimination deficits in isolation-reared rats without affecting discrimination in group-housed controls. By contrast, L-741,626 impaired novel object discrimination in group-housed rats, without affecting impairment in isolates. S33084 (0.16 mg/kg), S33138 and, less markedly, L741,626 reduced the locomotor hyperactivity in isolates without attenuating activity in group-housed controls. Selective blockade of dopamine D3 receptors reverses the visual recognition memory deficit and hyperactivity produced by isolation rearing. These data support further investigation of the potential use of dopamine D3 receptor antagonists to treat schizophrenia. © 2011 CINP.
Wurch T.,Institute Of Recherches Servier
Trends in biotechnology | Year: 2012
Recent advances in combinatorial protein engineering have made it possible to develop immunoglobulin (Ig)-based and non-Ig protein scaffolds that can potentially substitute for most whole antibody-associated properties and currently translate into biologicals with drug-like properties. During the past 10 years, the most validated scaffolds have reached the clinical development phase and, recently, one of them [Kalbitor(®) (Dyax)] has made it to the market, making these alternative scaffold proteins viable drug candidates in a post-antibody landscape. Interestingly, several scaffolds include an immune-active component as part of their therapeutic mode of action, which yielded spectacular clinical efficacy in some hematological malignancies. Here, we review the most recent clinical advances and analyze their benefits for patients. Copyright © 2012 Elsevier Ltd. All rights reserved.
Millan M.J.,Institute Of Recherches Servier
Pharmacology and Therapeutics | Year: 2010
Though l-3,4-dihydroxyphenylalanine (L-DOPA) is universally employed for alleviation of motor dysfunction in Parkinson's disease (PD), it is poorly-effective against co-morbid symptoms like cognitive impairment and depression. Further, it elicits dyskinesia, its pharmacokinetics are highly variable, and efficacy wanes upon long-term administration. Accordingly, "dopaminergic agonists" are increasingly employed both as adjuncts to L-DOPA and as monotherapy. While all recognize dopamine D2 receptors, they display contrasting patterns of interaction with other classes of monoaminergic receptor. For example, pramipexole and ropinirole are high efficacy agonists at D2 and D3 receptors, while pergolide recognizes D1, D2 and D3 receptors and a broad suite of serotonergic receptors. Interestingly, several antiparkinson drugs display modest efficacy at D2 receptors. Of these, piribedil displays the unique cellular signature of: 1), signal-specific partial agonist actions at dopamine D2 and D3 receptors; 2), antagonist properties at α2-adrenoceptors and 3), minimal interaction with serotonergic receptors. Dopamine-deprived striatal D2 receptors are supersensitive in PD, so partial agonism is sufficient for relief of motor dysfunction while limiting undesirable effects due to "over-dosage" of "normosensitive" D2 receptors elsewhere. Further, α2-adrenoceptor antagonism reinforces adrenergic, dopaminergic and cholinergic transmission to favourably influence motor function, cognition, mood and the integrity of dopaminergic neurones. In reviewing the above issues, the present paper focuses on the distinctive cellular, preclinical and therapeutic profile of piribedil, comparisons to pramipexole, ropinirole and pergolide, and the core triad of symptoms that characterises PD-motor dysfunction, depressed mood and cognitive impairment. The article concludes by highlighting perspectives for clarifying the mechanisms of action of piribedil and other antiparkinson agents, and for optimizing their clinical exploitation. © 2010 Elsevier Inc.
De Ceuninck F.,Institute Of Recherches Servier |
Fradin A.,Institute Of Recherches Servier |
Pastoureau P.,Institute Of Recherches Servier
Drug Discovery Today | Year: 2014
Osteoarthritis, a disease characterized by cartilage degradation, abnormal subchondral bone remodelling and some grade of inflammation, and sarcopenia, a condition of pathological muscle weakness associated with altered muscle mass, strength, and function, are prevalent disorders in elderly people. There is increasing evidence that decline in lower limb muscle strength is associated with knee or hip osteoarthritis in a context of pain, altered joint stability, maladapted postures and defective neuromuscular communication. At the cellular and molecular levels, chondrocytes and myoblasts share common pathological targets and pathways, and the close anatomical location of both cell types suggest a possibility of paracrine communication. In this review, we examine the relationship between osteoarthritis and sarcopenia in the musculoskeletal field, and discuss the potential advantage of concomitant therapies, or how each disorder may benefit from treatment of the other. © 2013 Elsevier Ltd.
Millan M.J.,Institute Of Recherches Servier
International Journal of Neuropsychopharmacology | Year: 2014
Major depression is a heterogeneous disorder, both in terms of symptoms, ranging from anhedonia to cognitive impairment, and in terms of pathogenesis, with many interacting genetic, epigenetic, developmental and environmental causes. Accordingly, it seems unlikely that depressive states could be fully controlled by a drug possessing one discrete mechanism of action and, in the wake of disappointing results with several classes of highly selective agent, multi-modal treatment concepts are attracting attention. As concerns pharmacotherapy, there are essentially two core strategies. First, multi-target antidepressants that act via two or more complementary mechanisms and, second, polypharmacy, which refers to co-administration of two distinct drugs, usually in separate pills. Both multi-target agents and polypharmacy ideally couple a therapeutically unexploited action to a clinically established mechanism in order to enhance efficacy, moderate side-effects, accelerate onset of action and treat a broader range of symptoms. The melatonin MT1/MT2 agonist and 5-HT2C antagonist, agomelatine, which is effective in the short-and long-term treatment of depression, exemplifies the former approach, while evidence-based polypharmacy is illustrated by the adjunctive use of second-generation antipsychotics with serotonin reuptake inhibitors for treatment of resistant depression. Histone acetylation and methylation, ghrelin signalling, inflammatory modulators, metabotropic glutamate-7 receptors and trace amine-associated-1 receptors comprise attractive substrates for new multi-target and polypharmaceutical strategies. The present article outlines the rationale underpinning multi-modal approaches for treating depression, and critically compares and contrasts the pros and cons of established and potentially novel multi-target vs polypharmaceutical treatments. On balance, the former appear the most promising for the elaboration, development and clinical implementation of innovative concepts for the more effective management of depression. © 2013 CINP.
Thollon C.,Institute Of Recherches Servier |
Vilaine J.-P.,Institute Of Recherches Servier
Advances in Pharmacology | Year: 2010
Heart rate (HR) is determined by the pacemaker activity of cells from the sinoatrial node (SAN), located in the right atria. Spontaneous electrical activity of SAN cells results from a diastolic depolarization (DD). Despite controversy in the exact contribution of funny current (If) in pacemaking, it is a major contributor of DD. If is an inward Na+/K+ current, activated upon hyperpolarization and directly modulated by cyclic adenosine monophosphate. The f-proteins are hyperpolarization-activated cyclic nucleotide-gated channels, HCN4 being the main isoform of SAN. Ivabradine (IVA) decreases DD and inhibits If in a use-dependent manner. Under normal conditions IVA selectively reduces HR and limits exercise-induced tachycardia, in animals and young volunteers. Reduction in HR with IVA both decreases myocardial oxygen consumption and increases its supply due to prolongation of diastolic perfusion time. In animal models and in human with coronary artery disease (CAD), IVA has anti-anginal and anti-ischemic efficacy, equipotent to classical treatments, Β-blockers, or calcium channel blockers. As expected from its selectivity for If, the drug is safe and well tolerated with minor visual side effects. As a consequence, IVA is the first inhibitor of If approved for the treatment of stable angina.Available clinical data indicate that IVA could improve the management of stable angina in all patients including those treated with Β-blockers. As chronic elevation of resting HR is an independent predictor of mortality, pure HR reduction by inhibition of If could, beyond the control of anti-anginal symptoms, improve the prognosis of CAD and heart failure; this therapeutic potential is currently under evaluation with IVA. © 2010 Elsevier Inc.
Feletou M.,Institute Of Recherches Servier
Journal of Cardiovascular Pharmacology | Year: 2016
The endothelium controls vascular tone not only by releasing various vasoactive substances but also by another pathway associated with the hyperpolarization of both endothelial and vascular smooth muscle cells and is termed endothelium-dependent hyperpolarization (EDH). These responses involve an increase in the endothelial intracellular Ca2+ concentration by the activation of transient receptor potential channels (predominantly TRPV4) followed by the opening of Ca2+-activated K+ channels of small and intermediate conductance (SKCa and IKCa). These channels show a distinct subcellular distribution. SKCa are widely distributed over the plasma membrane but segregates at sites of homocellular endothelial junctions, whereas IKCa are preferentially expressed in the myoendothelial projections. Following KCa activation, smooth muscle hyperpolarization is evoked by electrical coupling through myoendothelial gap junctions and/or by the potassium efflux that subsequently activates smooth muscle Kir2.1 and/or Na+/K+-ATPase. Alteration of the EDH contributes to the endothelial dysfunctions observed in various pathologies or conversely compensates for the loss in NO bioavailability. A better characterization of EDH should allow determining whether new druggable targets can be identified for the treatment of cardiovascular diseases. © Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved.