78 results on '"Palmier, C."'
Search Results
2. Differential activation of G proteins and extracellular signal-regulated kinase 1/2 phosphorylation via human dopamine D4.4 receptors: P175
- Author
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Heusler, P, Bruins, S L, Rauly-Lestienne, I, Palmier, C, and Cussac, D
- Published
- 2008
3. F15063, a potential antipsychotic with D2/D3 antagonist, 5-HT1A agonist and D4 partial agonist properties: (I) in vitro receptor affinity and efficacy profile
- Author
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Newman-Tancredi, A, Assié, M-B, Martel, J-C, Cosi, C, Slot, Bruins L, Palmier, C, Rauly-Lestienne, I, Colpaert, F, Vacher, B, and Cussac, D
- Published
- 2007
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4. BACKWARD NONLINEAR SMOOTHING DIFFUSIONS.
- Author
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ANDERSON, B. D. O., BISHOP, A. N., DEL MORAL, P., and PALMIER, C.
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STOCHASTIC differential equations ,MARGINAL distributions ,LINEAR equations ,DISTRIBUTION (Probability theory) ,KALMAN filtering - Abstract
We present a backward diffusion flow (i.e., a backward-in-time stochastic differential equation) whose marginal distribution at any (earlier) time is equal to the smoothing distribution when the terminal state (at a later time) is distributed according to the filtering distribution. This is a novel interpretation of the smoothing solution in terms of a nonlinear diffusion (stochastic) flow. This solution contrasts with, and complements, the (backward) deterministic flow of probability distributions (viz. a type of Kushner smoothing equation) studied in a number of prior works. A number of corollaries of our main result are given, including a derivation of the time-reversal of a stochastic differential equation, and an immediate derivation of the classical Rauch-Tung-Striebel smoothing equations in the linear setting. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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5. Facteurs d’altération de la qualité de vie sexuelle des patients en obésité morbide
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Lamat, H., Boirie, Y., Farigon, N., Gentes, E., Maras, J., Mulliez, A., Palmier, C., Pouget, M., and Miolanne, M.
- Published
- 2020
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6. Monoamine uptake inhibition by plasma from healthy volunteers after single oral doses of the antidepressant milnacipran
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Palmier, C., Puozzo, C., Lenehan, T., and Briley, M.
- Published
- 1989
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7. Évaluation des risques professionnels sur des opérations de chantiers de pavement
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Rouillon, A., Palmier, C., Bécret, E., Gilbert, J.-P., and Courtois, M.
- Published
- 2010
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8. P1014 Y a-t-il un intérêt à la corticothérapie anténatale au cours de la grossesse chez la diabétique après 34 SA ?
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Taillard, V., Marie Guedj, A., Cosma, V., Demattei, C., Palmier, C., Courtin, V., Mares, P., and Rodier, M.
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- 2013
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9. Validation of a multilevel sampling device to determine the vertical variability of chlorinated solvent in a contaminated aquifer.
- Author
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Barnier, C., Palmier, C., and Atteia, O.
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HETEROGENEITY ,POLLUTANTS ,AQUIFERS ,TETRACHLOROETHYLENE ,DICHLOROETHYLENE - Abstract
The vertical heterogeneity of contaminant concentrations in aquifers is well known, but obtaining representative samples is still a subject of debate. In this paper, the question arises from sites where numerous fully screened wells exist and there is a need to define the vertical distribution of contaminants. For this purpose, several wells were investigated with different techniques on a site contaminated with chlorinated solvents. A core-bored well shows that a tetrachloroethene (PCE) phase is sitting on and infiltrating a less permeable layer. Downstream of the cored well, the following sampling techniques were compared on fully screened wells: low flow pumping at several depths, pumping between packers and a new multilevel sampler for fully screened wells. Concerning low flow rate pumping, very low gradients were found, which may be due to the existence of vertical flow inside the well or in the gravel pack. Sampling between packers gave results comparable with the cores, separating a layer with PCE and trichloroethene from another one with cis1,2-dichloroethene and vinyl chloride as major compounds. Detailed sampling according to pumped volume shows that even between packers, cleaning of the inter-packer volume is necessary before each sampling. Lastly, the proposed new multilevel sampler gives results similar to the packers but has the advantages of much faster sampling and a constant vertical positioning, which is fairly important for long-term monitoring in highly stratified aquifers. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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10. Bénéfices et risques de la corticothérapie anténatale chez le nouveau-né de mère diabétique après 35 SA
- Author
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Taillard, V., Palmier, C., Guedj, A.M., Demattei, M.C., Courtin, V., Mares, P., and Rodier, M.
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- 2012
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11. F15063, a potential antipsychotic with D2/D3 antagonist, 5-HT1A agonist and D4 partial agonist properties: (I) in vitro receptor affinity and efficacy profile.
- Author
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Newman-Tancredi, A., Assié, M.-B., Martel, J.-C., Cosi, C., Slot, L. Bruins, Palmier, C., Rauly-Lestienne, I., Colpaert, F., Vacher, B., and Cussac, D.
- Subjects
DOPAMINE receptors ,ANTIPSYCHOTIC agents ,DRUG efficacy ,DIAGNOSIS of schizophrenia ,DRUG therapy for psychoses ,MEDICAL experimentation on humans - Abstract
Background and purpose:Combining 5-HT
1A receptor activation with dopamine D2 /D3 receptor blockade should improve negative symptoms and cognitive deficits in schizophrenia. We describe the in vitro profile of F15063 (N-[(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)ethyl]-3-(cyclopent-1-enyl)-benzylamine).Experimental approach:F15063 was characterised in tests of binding affinity and in cellular models of signal transduction at monoamine receptors.Key results:Affinities (receptor and pKi values) of F15063 were: rD2 9.38; hD2L 9.44; hD2S 9.25; hD3 8.95; hD4 8.81; h5-HT1A 8.37. F15063 had little affinity (40-fold lower than D2 ) at other targets. F15063 antagonised dopamine-activated G-protein activation at hD2 , rD2 and hD3 receptors with potency (pKb values 9.19, 8.29 and 8.74 in [35 S]GTPγS binding experiments) similar to haloperidol. F15063 did not exhibit any hD2 receptor agonism, even in tests of ERK1/2 phosphorylation and G-protein activation in cells with high receptor expression. In contrast, like (±)8-OH-DPAT, F15063 efficaciously activated h5-HT1A (Emax 70%, pEC50 7.57) and r5-HT1A receptors (52%, 7.95) in tests of [35 S]GTPγS binding, cAMP accumulation (90%, 7.12) and ERK1/2 phosphorylation (93%, 7.13). F15063 acted as a partial agonist for [35 S]GTPγS binding at hD4 (29%, 8.15) and h5-HT1D receptors (35%, 7.68). In [35 S]GTPγS autoradiography, F15063 activated G-proteins in hippocampus, cortex and septum (regions enriched in 5-HT1A receptors), but antagonised quinelorane-induced activation of D2 /D3 receptors in striatum.Conclusions and implications:F15063 antagonised dopamine D2 /D3 receptors, a property underlying its antipsychotic-like activity, whereas activation of 5-HT1A and D4 receptors mediated its actions in models of negative symptoms and cognitive deficits of schizophrenia (see companion papers).British Journal of Pharmacology (2007) 151, 237–252. doi:10.1038/sj.bjp.0707158; published online 20 March 2007 [ABSTRACT FROM AUTHOR]- Published
- 2007
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12. Topical Ketoconazole for Infantile Seborrhoeic Dermatitis.
- Author
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Taieb, A., Legrain, V., Palmier, C., Lejean, S., Six, M., and Maleville, J.
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- 1990
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13. ChemInform Abstract: Design and Synthesis of New Potent, Silent 5-HT1A Antagonists by Covalent Coupling of Aminopropanol Derivatives with Selective Serotonin Reuptake Inhibitors.
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Perez, M., Pauwels, P. J., Pallard-Sigogneau, I., Fourrier, C., Chopin, P., Palmier, C., Colovray, V., and Halazy, S.
- Published
- 1999
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14. Design and synthesis of new potent, silent 5-HT 1A antagonists by covalent coupling of aminopropanol derivatives with selective serotonin reuptake inhibitors
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Perez, M, Pauwels, P.J, Pallard-Sigogneau, I, Fourrier, C, Chopin, P, Palmier, C, Colovray, V, and Halazy, S
- Published
- 1998
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15. Arylpiperazide derivatives of phenylpiperazines as a new class of potent and selective 5-HT 1B receptor antagonists
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Jorand-Lebrun, C., Pauwels, P.J., Palmier, C., Chopin, P., Moret, C., Marien, M., and Halazy, S.
- Published
- 1997
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16. Synthesis, binding affinity and intrinsic activity of new anilide derivatives of serotonin at human 5-HT 1D receptors
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Perez, M, Ayerbe, N, Fourrier, C, Sigogneau, I, Pauwels, PJ, Palmier, C, John, GW, Valentin, JP, and Halazy, S
- Published
- 1997
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17. Inhibition by 5-HT of forskolin-induced cAMP Formation in the renal opossum Epithelial cell line OK: Mediation by a 5-HT 1B like receptor and antagonism by methiothepin
- Author
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Pauwels, P.J. and Palmier, C.
- Published
- 1994
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18. Effects of prolonged administration of milnacipran, a new antidepressant, on receptors and monoamine uptake in the brain of the rat
- Author
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Assie, M.B., Charveron, M., Palmier, C., Puozzo, C., Moret, C., and Briley, M.
- Published
- 1992
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19. How Efficacious are 5-HT1B/D Receptor Ligands: an Answer from GTPγS Binding Studies with Stably Transfected C6-glial Cell Lines
- Author
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PAUWELS, P.J., TARDIF, S., PALMIER, C., WURCH, T., and COLPAERT, F.C.
- Published
- 1997
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20. Differential effects of itanoxone — A new hypolipidemic and hypouricemic drug — On platelet and vascular prostaglandin generation in rats
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Livio, M., Palmier, C., Villa, S., Maynadier, B., Delhon, A., Lauressergues, H., and De Gaetano, G.
- Published
- 1981
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21. ChemInform Abstract: Synthesis and Structure-Activity Relationships of 5-Substituted Tryptamine Derivatives of o-Tolylpiperazine as Agonists at 5-HT1D Receptors.
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PEREZ, M., PAUWELS, P. J., PALMIER, C., JOHN, G. W., VALENTIN, J. P., and HALAZY, S.
- Published
- 1996
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22. ChemInform Abstract: Synthesis and Serotonergic Activity of Arylpiperazide Derivatives of Serotonin: Potent Agonists for 5-HT1D Receptors.
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PEREZ, M., FOURRIER, C., SIGOGNEAU, I., PAUWELS, P. J., PALMIER, C., JOHN, G. W., VALENTIN, J.-P., and HALAZY, S.
- Published
- 1995
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23. ChemInform Abstract: 5-O-Carboxymethyl Piperazide Derivatives of Serotonin: A New Class of Potent and Selective 5-HT1D Receptor Agonists.
- Author
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PEREZ, M., PAUWELS, P., PALMIER, C., JOHN, G. W., VALENTIN, J.-P., and HALAZY, S.
- Published
- 1995
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24. Plasma viscosity and biochemical parameters in the “fatty” rat
- Author
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Stoltz, J.F., Gaillard, S., Dehlon, A., Palmier, C., Benisti, G., Lauressergues, H., and Presles, J.M.
- Published
- 1981
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25. Molecular cloning of a Chinese hamster lung (CHL) fibroblast cDNA encoding a 5-hydroxytryptamine 1B receptor
- Author
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Wurch, T., Palmier, C., Colpaert, F.C., and Pauwels, P.J.
- Published
- 1995
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26. Stimulation of cloned human 5-HT1Dβ receptor sites in permanently transfected C6-glial cells promotes cell proliferation
- Author
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Pauwels, P.J., Wurch, T., Palmier, C., and Colpaert, F.C.
- Published
- 1995
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27. Identification of Ethical Issues and Practice Recommendations Regarding the Use of Robotic Coaching Solutions for Older Adults: Narrative Review.
- Author
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Palmier C, Rigaud AS, Ogawa T, Wieching R, Dacunha S, Barbarossa F, Stara V, Bevilacqua R, and Pino M
- Subjects
- Humans, Aged, Mentoring methods, Mentoring ethics, Quality of Life, Robotics ethics
- Abstract
Background: Technological advances in robotics, artificial intelligence, cognitive algorithms, and internet-based coaches have contributed to the development of devices capable of responding to some of the challenges resulting from demographic aging. Numerous studies have explored the use of robotic coaching solutions (RCSs) for supporting healthy behaviors in older adults and have shown their benefits regarding the quality of life and functional independence of older adults at home. However, the use of RCSs by individuals who are potentially vulnerable raises many ethical questions. Establishing an ethical framework to guide the development, use, and evaluation practices regarding RCSs for older adults seems highly pertinent., Objective: The objective of this paper was to highlight the ethical issues related to the use of RCSs for health care purposes among older adults and draft recommendations for researchers and health care professionals interested in using RCSs for older adults., Methods: We conducted a narrative review of the literature to identify publications including an analysis of the ethical dimension and recommendations regarding the use of RCSs for older adults. We used a qualitative analysis methodology inspired by a Health Technology Assessment model. We included all article types such as theoretical papers, research studies, and reviews dealing with ethical issues or recommendations for the implementation of these RCSs in a general population, particularly among older adults, in the health care sector and published after 2011 in either English or French. The review was performed between August and December 2021 using the PubMed, CINAHL, Embase, Scopus, Web of Science, IEEE Explore, SpringerLink, and PsycINFO databases. Selected publications were analyzed using the European Network of Health Technology Assessment Core Model (version 3.0) around 5 ethical topics: benefit-harm balance, autonomy, privacy, justice and equity, and legislation., Results: In the 25 publications analyzed, the most cited ethical concerns were the risk of accidents, lack of reliability, loss of control, risk of deception, risk of social isolation, data confidentiality, and liability in case of safety problems. Recommendations included collecting the opinion of target users, collecting their consent, and training professionals in the use of RCSs. Proper data management, anonymization, and encryption appeared to be essential to protect RCS users' personal data., Conclusions: Our analysis supports the interest in using RCSs for older adults because of their potential contribution to individuals' quality of life and well-being. This analysis highlights many ethical issues linked to the use of RCSs for health-related goals. Future studies should consider the organizational consequences of the implementation of RCSs and the influence of cultural and socioeconomic specificities of the context of experimentation. We suggest implementing a scalable ethical and regulatory framework to accompany the development and implementation of RCSs for various aspects related to the technology, individual, or legal aspects., (©Cécilia Palmier, Anne-Sophie Rigaud, Toshimi Ogawa, Rainer Wieching, Sébastien Dacunha, Federico Barbarossa, Vera Stara, Roberta Bevilacqua, Maribel Pino. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 18.06.2024.)
- Published
- 2024
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28. e-VITA study protocol: EU-Japan virtual coach for smart aging.
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Bevilacqua R, Stara V, Amabili G, Margaritini A, Benadduci M, Barbarossa F, Maranesi E, Rigaud AS, Dacunha S, Palmier C, Moller J, Browne R, Ogawa T, and Wieching R
- Subjects
- Humans, Aged, Japan, Healthy Lifestyle, Smartphone, Randomized Controlled Trials as Topic, Quality of Life, Aging psychology
- Abstract
Aim: The aim of this study is to report a trial protocol for assessing the improvement of older adults' well-being, promoting active and healthy aging, and reducing the risks of social exclusion, using a virtual coach., Background: Increased longevity brings with it reduced autonomy and independence, and it is therefore necessary to act with preventive measures that can promote active and healthy aging. With the development of technology, new tools have appeared, including virtual coaches, which can enable people to lead a healthy lifestyle by identifying individual needs and goals and providing personalized recommendations and advice. However, it is important that these coaches take into consideration the inter-individual and cross-cultural differences of each person., Design: A randomized controlled trial is proposed., Methods: This study will recruit 240 healthy subjects aged 65 years and older. Participants will be assigned to an experimental group that will receive the e-VITA system or to the control group that will receive an information booklet only. The primary outcome measure is the person's quality of life (QoL). Data will be collected at baseline, 3 months after the trial, and at the end of the trial, after 6 months., Discussion: This study will evaluate the effectiveness of the e-VITA system, consisting of a virtual coach, several sensors for monitoring, a smartphone for use at home, and a booklet, in improving the older person's quality of life. The increased perceived well-being will also be linked to improvements in other areas of the person's life, psychological and cognitive status, the area of sociality, nutrition, and eHealth literacy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Bevilacqua, Stara, Amabili, Margaritini, Benadduci, Barbarossa, Maranesi, Rigaud, Dacunha, Palmier, Moller, Browne, Ogawa and Wieching.)
- Published
- 2024
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29. Technology-Enabled Senior Living: A Preliminary Report on Stakeholder Perspectives.
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Stara V, Maranesi E, Möller J, Palmier C, Ogawa T, Browne R, Luc M, Wieching R, Boudy J, and Bevilacqua R
- Abstract
Background: The integration of stakeholders is crucial in developing smart living technologies to support the autonomy of elderly populations. Despite the clear benefits of these technologies, there remains a significant gap in comprehensive research., Methods: This study presents the viewpoints of 19 stakeholders from Europe and Japan, focusing on the sustainability of smart living solutions for Active and Healthy Ageing (AHA). Data were gathered through qualitative semi-structured interviews and analysed using a Framework Analysis approach., Results: Analysis of the interviews revealed six key sustainability categories: addressing the unmet needs of older adults, functionalities of the smart living coach, integration within organizations, identified barriers, financial considerations, and the social role of the smart living coach., Conclusions: This research underscores the importance of evaluating user needs through the involvement of various stakeholders, including the elderly, their caregivers, professionals, technicians, service providers, and government bodies. Collaborative efforts are essential to generate new evidence demonstrating the value of smart living solutions in facilitating Active and Healthy Ageing.
- Published
- 2024
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30. Toward Innovation in Healthcare: An Analysis of the Digital Behavior of Older People in Europe and Japan for the Introduction of a Technological Coaching System.
- Author
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Möller J, Stara V, Amabili G, Barbarossa F, Riccardi GR, Martella C, Di Donna V, Palmier C, Ogawa T, Luc M, Wieching R, Maranesi E, and Bevilacqua R
- Abstract
(1) Background: The increasing older population and demographic shifts highlight the need to understand the digital profiles of older adults, a pivotal factor in developing innovative technologies like the e-VITA virtual coach. This personalized coach provides recommendations for sustainable well-being in a smart home environment. (2) Methods: This study focuses on analyzing the characteristics of older individuals categorized as Internet users (onliners) and non-users (offliners). European Social Survey data from 2021 were utilized for European analysis, determining Internet usage based on frequency. Offliners are defined as users who never use the Internet, and onliners as those who use it, albeit with different frequencies. In Japan, data from the 9th International Comparative Survey on the Lives and Attitudes of the Elderly were employed, based on the responses of 1367 subjects, which defined onliners as individuals using communication devices and offliners as those not utilizing fax machines, cell phones, or the Internet. (3) Results: This paper presents a primary analysis of older end-user context and perspectives, outlining effective strategies for the diffusion of an active and healthy aging coaching system in the market and society. (4) Conclusions: the study emphasizes the importance of analyzing digital behavior in any user-centered design approach to ensure the system's acceptance after deployment.
- Published
- 2024
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31. Intrinsic Capacity and Active and Healthy Aging Domains Supported by Personalized Digital Coaching: Survey Study Among Geriatricians in Europe and Japan on eHealth Opportunities for Older Adults.
- Author
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Stara V, Soraci L, Takano E, Kondo I, Möller J, Maranesi E, Luzi R, Riccardi GR, Browne R, Dacunha S, Palmier C, Wieching R, Ogawa T, and Bevilacqua R
- Subjects
- Humans, Aged, Geriatricians, Japan, Europe, Healthy Aging, Mentoring, Telemedicine
- Abstract
Background: The worldwide aging trend requires conceptually new prevention, care, and innovative living solutions to support human-based care using smart technology, and this concerns the whole world. Enabling access to active and healthy aging through personalized digital coaching services like physical activity coaching, cognitive training, emotional well-being, and social connection for older adults in real life could offer valuable advantages to both individuals and societies. A starting point might be the analysis of the perspectives of different professionals (eg, geriatricians) on such technologies. The perspectives of experts in the sector may allow the individualization of areas of improvement of clinical interventions, supporting the positive perspective pointed out by the intrinsic capacity framework., Objective: The overall aim of this study was to explore the cross-national perspectives and experiences of different professionals in the field of intrinsic capacity, and how it can be supported by eHealth interventions. To our knowledge, this is the first study to explore geriatric care providers' perspectives about technology-based interventions to support intrinsic capacity., Methods: A survey involving 20 geriatricians or clinical experts in the fields of intrinsic capacity and active and healthy aging was conducted in Italy, France, Germany, and Japan between August and September 2021., Results: The qualitative findings pointed out relevant domains for eHealth interventions and provided examples for successful practices that support subjective well-being under the intrinsic capacity framework (the benefits offered by personalized interventions, especially by promoting health literacy but avoiding intrusiveness). Moreover, eHealth interventions could be used as a bridge that facilitates and enables social engagement; an instrument that facilitates communication between doctors and patients; and a tool to enrich the monitoring actions of medical staff., Conclusions: There is an unexplored and significant role for such geriatric perspectives to help the development process and evaluate the evidence-based results on the effectiveness of technologies for older people. This is possible only when clinicians collaborate with data scientists, engineers, and developers in order to match the complex daily needs of older adults., (©Vera Stara, Luca Soraci, Eiko Takano, Izumi Kondo, Johanna Möller, Elvira Maranesi, Riccardo Luzi, Giovanni Renato Riccardi, Ryan Browne, Sébastien Dacunha, Cecilia Palmier, Rainer Wieching, Toshimi Ogawa, Roberta Bevilacqua. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 12.10.2023.)
- Published
- 2023
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32. User Perceptions and Needs Analysis of a Virtual Coach for Active and Healthy Ageing-An International Qualitative Study.
- Author
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Möller J, Bevilacqua R, Browne R, Shinada T, Dacunha S, Palmier C, Stara V, Maranesi E, Margaritini A, Takano E, Kondo I, Watanabe S, Ahmadi M, Wieching R, and Ogawa T
- Subjects
- Aged, Humans, Pandemics prevention & control, Qualitative Research, COVID-19 epidemiology, Healthy Aging, Mentoring
- Abstract
Virtual coaching systems show great potential for meeting the challenges of demographic change. However, the proportion of older users in the field of digital technologies is far behind that of younger people. As part of the e-VITA project, semi-structured interviews were conducted in Japan, France, Italy and Germany with 58 people aged 65 and over, and the content was analyzed with the aim of obtaining information about how older adults organize their everyday lives, also with regard to the COVID-19 pandemic, how they deal with their health, what role digital technologies play in the lives of the interviewees and why they oppose progressive digitization. Second, the survey asked why the older adults oppose a virtual coach, which is to be developed in the e-VITA project to support older adults in healthy and active aging, and what barriers they see in a possible implementation. It was found that older respondents lead active, varied lives and that the COVID-19 pandemic contributed to the increased use of digital solutions. In addition, respondents were consciously addressing their own health. With regard to a virtual coach, barriers were seen primarily in the area of data security and sharing. It can be concluded from this that heterogeneity among older user groups should be taken into account when developing virtual coaches. In addition, aspects of data security and data protection should be presented in a clearly understandable and transparent manner.
- Published
- 2022
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33. [(3)H]-F13640, a novel, selective and high-efficacy serotonin 5-HT(1A) receptor agonist radioligand.
- Author
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Heusler P, Palmier C, Tardif S, Bernois S, Colpaert FC, and Cussac D
- Subjects
- Animals, Binding, Competitive, CHO Cells, Cell Culture Techniques, Cell Membrane drug effects, Cell Membrane metabolism, Cricetinae, Cricetulus, Humans, Protein Binding, Radioligand Assay, Receptor, Serotonin, 5-HT1A biosynthesis, Tritium, Piperidines pharmacology, Pyridines pharmacology, Receptor, Serotonin, 5-HT1A metabolism, Serotonin 5-HT1 Receptor Agonists pharmacology
- Abstract
F13640 is a selective and high-efficacy serotonin 5-HT(1A) receptor agonist that demonstrates outstanding analgesic potential in different animal models. Here, we use the radiolabelled compound to further characterise its binding properties at 5-HT(1A) receptors. F13640 was tritium-labelled to 47 and 64 Ci/mmol specific activity and used as radioligand at membrane preparations of CHO cells expressing human (h) 5-HT(1A) receptors. The K (d) of [(3)H]-F13640 was 1.8 nM at h5-HT(1A) receptors as determined from saturation binding experiments. In association time-course experiments, k (obs) of [(3)H]-F13640 was 0.06 min(-1). Dissociation experiments performed in the presence of unlabelled F13640 as competing ligand yielded a k (off) value of 0.05 min(-1), resulting in a calculated K (d) of 1.4 nM. In comparison, [(3)H]-8-OH-DPAT had a k (obs) of 0.50 min(-1), a k (off) of 0.25 min(-1) and a calculated K (d) of 0.37 nM. Surprisingly, [(3)H]-F13640 dissociation kinetics were distinctly slower in the presence of WAY-100635 and spiperone as competing ligands when compared with the agonist competitors, F13640 and (+)8-OH-DPAT. The competitive binding profile of [(3)H]-F13640 with eight chemically diverse 5-HT(1A) receptor agonists and antagonists correlated highly (r = 0.996) with that of [(3)H]-8-OH-DPAT. In conclusion, [(3)H]-F13640 is a potent agonist radioligand at 5-HT(1A) receptors and may be a useful tool in pharmacological studies at native and recombinant 5-HT(1A) receptors. In addition, [(3)H]-F13640 dissociates more slowly from h5-HT(1A) receptors than [(3)H]-8-OH-DPAT, a kinetic property that might be related to its powerful analgesic effects as observed in vivo.
- Published
- 2010
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34. Mutant 5-hydroxytryptamine 1A receptor D116A is a receptor activated solely by synthetic ligands with a rich pharmacology.
- Author
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Cussac D, Palmier C, Finana F, De Vries L, Tardif S, Léger C, Bernois S, and Heusler P
- Subjects
- 8-Hydroxy-2-(di-n-propylamino)tetralin metabolism, 8-Hydroxy-2-(di-n-propylamino)tetralin pharmacology, Alanine genetics, Amino Acid Substitution genetics, Animals, Aspartic Acid genetics, Binding, Competitive genetics, CHO Cells, Cricetinae, Cricetulus, Female, Humans, Ligands, Mutagenesis, Site-Directed methods, Piperazines metabolism, Piperazines pharmacology, Protein Binding drug effects, Protein Binding genetics, Pyridines metabolism, Pyridines pharmacology, Serotonin Receptor Agonists metabolism, Serotonin Receptor Agonists pharmacology, Xenopus laevis, Receptor, Serotonin, 5-HT1A genetics, Receptor, Serotonin, 5-HT1A metabolism
- Abstract
Like other biogenic amine G protein-coupled receptors, mutation of the conserved aspartatic residue into alanine at position 116 (D116A(3.32)) in the 5-hydroxytryptamine (5-HT)(1A) receptor greatly affects 5-HT binding and signal transduction. [(3)H]8-Hydroxy-2-dipropylaminotetralin (8-OH-DPAT) and [(3)H]-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride (WAY100,635) are capable to bind the 5-HT(1A)-D116A mutant and, using these radioligands, we show here that this mutation dramatically reduces the affinities of the selective 5-HT(1A) agonists N-(3-chloro-4-fluorobenzoyl)-4-fluoro-4-[(5-methylpyridin-2-yl)-methylamino methyl]piperidine (F13640), 3-chloro-4-fluorophenyl-(4-fluorophenyl-4-{[(5-methyl-6 methylamino-pyridin-2-ylmethyl)-amino]-methyl}-piperidin-1-yl-methanone (F13714), and 2-[5-[3-(4-methylsulfonylamino)benzyl-1,4-oxadiazol-5-yl]-1H-indole-3-yl]ethylamine (L694247) and that of 5-carboxamidotryptamine. Although to a lesser extent, the binding of buspirone, (+)-flesinoxan, (-)-pindolol, and (-)-8-OH-DPAT are also highly decreased. In contrast, affinities of the 5-HT(1A) ligands WAY100,635, spiperone, (-)-4-(dipropylamino)-1,3,4,5-tetrahydrobenz {c,d}indole-6-carboxamide (LY228,729), and 1-[2-(4-fluorobenzoylamino)ethyl]-4-(7-methoxynaphtyl) piperazine (S14506) and the prototypical 5-HT(1A) agonist (+)-8-OH-DPAT are only slightly affected by the mutation, suggesting a moderate contribution of Asp116 to the binding pocket for these latter. Furthermore, LY228,729, S14506, and (+)-8-OH-DPAT induce a potent and efficacious coupling of the 5-HT(1A)-D116A receptor to G protein activation as measured by Ca(2+) mobilization and guanosine 5'-O-(3-[(35)S]thio)triphosphate binding in Chinese hamster ovary cells as well as by G protein-coupled inwardly rectifying potassium channel current activation in Xenopus laevis oocytes. It is interesting that the selective 5-HT(1A) antagonist WAY100,635 shows potent partial agonist activity at the 5-HT(1A)-D116A mutant, whereas spiperone maintains its inverse agonist properties. The pharmacological approach reported here re-evaluates the binding and functional properties of the 5-HT(1A)-D116A receptor and describes for the first time this mutant as a receptor activated solely by synthetic ligands (RASSL), with a rich pharmacology. By bioengineering animal models incorporating this RASSL, one may further explore the role of 5-HT(1A) receptor signaling in the central nervous system as well as G(i) protein-mediated signaling pathways in other tissues.
- Published
- 2009
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35. Activation of G proteins and extracellular signal-regulated kinase 1/2 phosphorylation via human dopamine D4.4 receptors: differential pathway-dependent potencies of receptor agonists.
- Author
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Heusler P, Bruins Slot L, Rauly-Lestienne I, Palmier C, Tardif S, Tourette A, Ailhaud MC, and Cussac D
- Subjects
- Animals, Antipsychotic Agents pharmacology, Binding, Competitive, CHO Cells, Cricetinae, Cricetulus, Dopamine pharmacology, Dopamine Antagonists pharmacology, Dose-Response Relationship, Drug, Enzyme Activation, Epinephrine pharmacology, GTP-Binding Proteins metabolism, Guanosine 5'-O-(3-Thiotriphosphate) metabolism, Humans, Norepinephrine pharmacology, Phosphorylation, Protein Binding, Radioligand Assay, Receptors, Dopamine D4 agonists, Receptors, Dopamine D4 antagonists & inhibitors, Dopamine Agonists pharmacology, GTP-Binding Proteins agonists, Mitogen-Activated Protein Kinase 1 metabolism, Mitogen-Activated Protein Kinase 3 metabolism, Receptors, Dopamine D4 physiology
- Abstract
Agonist activity at recombinant human dopamine D4.4 receptors was compared in stably transfected CHO cells using two functional readouts: G protein activation by [35S]GTPgammaS binding and phosphorylation of extracellular signal-regulated kinase 1/2 (pERK1/2). Results with a large series of agonists reveal markedly higher relative agonist efficacy in the pERK1/2 assay compared with [35S]GTPgammaS binding, while potencies were generally higher in the latter readout. Whereas efficacies were highly correlated when comparing both tests, potencies determined using the pERK1/2 assay were neither correlated with those for G protein activation nor with binding affinities. In order to examine if these differences may be attributable to distinct assay conditions (5 min incubation for pERK1/2 compared with binding equilibrium conditions for [35S]GTPgammaS), selected compounds were tested in a modified short-duration [35S]GTPgammaS binding assay. In these experiments, potencies were generally reduced; however, compounds exhibiting comparably high potency in the pERK1/2 assay were not affected by this duration-dependent potency shift. We conclude that assay parameters such as signal amplification and incubation time have to be considered with respect to the appropriate choice of experimental approaches that best reflect agonist activity at dopamine D4 receptors in vivo.
- Published
- 2009
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36. Action of novel antipsychotics at human dopamine D3 receptors coupled to G protein and ERK1/2 activation.
- Author
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Bruins Slot LA, Palmier C, Tardif S, and Cussac D
- Subjects
- Animals, CHO Cells, Cricetinae, Cricetulus, Dopamine Agonists pharmacology, Dopamine Antagonists pharmacology, Dose-Response Relationship, Drug, Drug Interactions, Enzyme Activation drug effects, Guanosine 5'-O-(3-Thiotriphosphate) pharmacokinetics, Humans, Phosphorylation drug effects, Protein Binding drug effects, Transfection, Antipsychotic Agents pharmacology, Extracellular Signal-Regulated MAP Kinases metabolism, GTP-Binding Proteins metabolism, Gene Expression drug effects, Receptors, Dopamine D3 physiology
- Abstract
The effects of new generation antipsychotic drugs (APDs) targeting dopamine D(2) and serotonin 5-HT(1A) receptors were compared with typical and atypical APDs on phosphorylation of extracellular signal-regulated kinase 1/2 (ERK 1/2) and measures of G protein activation in CHO cell lines stably expressing the human dopamine D(3) receptor. The preferential dopamine D(3) agonists (+)-7-OH-DPAT and PD128907, like dopamine and quinelorane, efficaciously stimulated ERK 1/2 phosphorylation at dopamine D(3) receptors. In contrast, in [(35)S]GTPgammaS binding experiments, (+)-7-OH-DPAT exhibited partial agonist properties, while PD128907 and quinelorane maintained full agonist properties. The preferential dopamine D(3) ligand BP 897 and the antidyskinetic sarizotan partially activated ERK 1/2 phosphorylation while exerting no agonist activity on GTPgammaS binding, suggesting signal amplification at the MAP kinase level. Antipsychotics differed in their ability to inhibit both agonist-stimulated GTPgammaS binding and ERK 1/2 phosphorylation, but all typical and atypical compounds tested acted as dopamine D(3) receptor antagonists with the exception of n-desmethylclozapine, the active metabolite of clozapine, which partially activated dopamine D(3) receptor-mediated ERK 1/2 phosphorylation. Among the new generation dopamine D(2)/serotonin 5-HT(1A) antipsychotics, only F 15063 and SLV313 acted as pure dopamine D(3) receptor antagonists, bifeprunox was highly efficacious whereas SSR181507 and aripiprazole showed marked partial agonist properties for ERK 1/2 phosphorylation. In contrast, in the GTPgammaS binding study, aripiprazole was devoid of agonist properties and bifeprunox, and to an even lesser extent SSR181507, only weakly stimulated GTPgammaS binding. In summary, these findings underline the differences of dopamine D(3) properties of new generation antipsychotics which may need to be considered in understanding their diverse therapeutic actions.
- Published
- 2007
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37. Pharmacological characterization of protease activated receptor-1 by a serum responsive element-dependent reporter gene assay: major role of calmodulin.
- Author
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De Vries L, Palmier C, Finana F, Le Grand B, Perez M, and Cussac D
- Subjects
- Animals, Binding, Competitive, Biological Assay, COS Cells, Calcium-Calmodulin-Dependent Protein Kinases genetics, Calmodulin antagonists & inhibitors, Chlorocebus aethiops, Egtazic Acid analogs & derivatives, Egtazic Acid pharmacology, GTP-Binding Protein alpha Subunits metabolism, Ligands, Luciferases metabolism, Oligopeptides pharmacology, Pyrroles pharmacology, Quinazolines pharmacology, RGS Proteins metabolism, Radioligand Assay, Receptor, PAR-1 genetics, Sesterterpenes, Sulfonamides pharmacology, Terpenes pharmacology, Thrombin pharmacology, Transfection, Platelet Aggregation Inhibitors, Calcium-Calmodulin-Dependent Protein Kinases metabolism, Calmodulin metabolism, Genes, Reporter genetics, Luciferases genetics, Receptor, PAR-1 metabolism, Serum Response Element genetics
- Abstract
We studied the protease activated receptor-1 coupling to a serum response element (SRE)-dependent luciferase activity readout in transfected COS-7 cells. Thrombin, with a pEC50 of 10.5, was 3000-fold more potent than the peptide agonists SFLLR and its derived compound C721-40 in stimulating luciferase activity, although the three agonists exhibited similar efficacy at the maximal concentration tested. Interestingly, SFLLR- and C721-40-induced luciferase activity was biphasic, suggesting that at least two populations of G proteins couple to the receptor. Further pharmacological characterization of this system was performed using selective protease activated receptor-1 antagonists. SCH203099 and ER-112787 blocked SFLLR-induced luciferase activity with similar potencies (pK(B) of 7), slightly higher than that exhibited by an arylisoxazole derivative compound from Merck (pK(B) of 6.1). These values correlated with their affinities established by competition binding experiments using [3H]-C721-40 as radioligand for protease activated receptor-1. Transduction mechanisms of protease activated receptor-1 coupling to SRE-dependent luciferase activity were examined using specific inhibitors. The Ca2+ chelator BAPTA-AM, as well as the calmodulin inhibitors W-7 and ophiobolin A, robustly inhibited SFLLR-induced SRE activation. Overexpression of RGS2 and a dominant negative rhoA protein abolished the SFLLR signal in an additive manner, suggesting a major role of Gq and G12/13 proteins. Furthermore, inhibition of phospholipase C, MAP-kinases, phosphatidyl inositol-3 kinase, rho-kinase and Ca2+/calmodulin-dependent protein kinases, all downstream effectors of Gq and G12/13, partially blocked the SFLLR-induced luciferase signal. Taken together, this SRE-luciferase assay reveals a complex network of transduction pathways of protease activated receptor-1 in accordance with the pleiotrophic action of thrombin.
- Published
- 2006
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38. Constitutive coupling of a chimeric dopamine D2/alpha 1B receptor to the phospholipase C pathway: inverse agonism to silent antagonism by neuroleptic drugs.
- Author
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Wurch T, Boutet-Robinet EA, Palmier C, Colpaert FC, and Pauwels PJ
- Subjects
- Animals, Benzamides pharmacology, CHO Cells, Calcium metabolism, Cricetinae, Digitonin pharmacology, Dopamine metabolism, Female, Guanosine 5'-O-(3-Thiotriphosphate) metabolism, Inositol Phosphates metabolism, Kinetics, Ligands, Radioligand Assay, Receptors, Dopamine D2 agonists, Receptors, Dopamine D2 genetics, Recombinant Fusion Proteins metabolism, Transfection, Antipsychotic Agents pharmacology, Dopamine Agonists pharmacology, Dopamine Antagonists pharmacology, Receptors, Dopamine D2 metabolism, Type C Phospholipases metabolism
- Abstract
Neuroleptic drugs have been suggested to act as inverse agonists at the dopamine D2 receptor, but no link between therapeutic efficacy and ligand's intrinsic activity could be determined. Since the resolving capacity to monitor inverse agonism at dopamine D2 receptors is limited, we speculated that receptor constitutive activation could be enhanced by constructing chimeric D2/alpha 1B receptors. Marked inverse agonist responses with a series of dopamine antagonists were obtained by: 1) exchange of the D 2short receptor's 3ICL by that of the alpha 1B-adrenoceptor, 2) incorporation of an activating mutation (Ala 279 Glu) in the distal portion of its 3ICL, and 3) coexpression with a G alpha11 protein. This chimeric D2/alpha 1B receptor construct displayed a ligand binding profile comparable to that of the wild-type (wt) D 2short receptor and an effector activation profile close to that of the wt alpha 1B-adrenoceptor. Most of the dopamine antagonists attenuated by -54 to -59% basal inositol phosphates (IP) formation, thus clearly acting as inverse agonists. Ziprasidone behaved as a silent antagonist (+5% versus basal IP level) and antagonized both dopamine-mediated (pK B, 7.61) and tropapride-mediated (pK B, 8.52) IP responses. Clozapine, olanzapine, and raclopride displayed partial inverse agonist properties (-31, -67, and -71% versus tropapride, respectively), whereas bromerguride (+63%) and cis-(+)-5-methoxy-1-methyl-2-(di-n-propylamino tetralin) [(+)-UH 232] (+88%) demonstrated positive agonism. In conclusion, analyses with the chimeric D2/alpha 1B Ala 279 Glu 3ICL receptor construct suggest that neuroleptic drugs can be differentiated on the basis of their intrinsic activity, as they can either activate, inhibit, or be silent at this receptor construct.
- Published
- 2003
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39. Induction of a high-affinity ketanserin binding site at the 5-Hydroxytryptamine(1B) receptor by modification of its carboxy-terminal intracellular portion.
- Author
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Wurch T, Palmier C, and Pauwels PJ
- Subjects
- Animals, Binding Sites, COS Cells, Cells, Cultured, Humans, Ligands, Receptor, Serotonin, 5-HT1B, Receptor, Serotonin, 5-HT2A, Receptors, Serotonin genetics, Recombinant Fusion Proteins metabolism, Ketanserin pharmacology, Receptors, Serotonin metabolism, Serotonin Antagonists pharmacology
- Abstract
Two chimeric 5-hydroxytryptamine (5-HT) receptors were constructed by exchanging the C-terminal portion of the human (h) 5-HT(1B) receptor with the equivalent domain of the h 5-HT(2A) receptor (5-HT(1B/2A)) or with this domain truncated from its last 44 amino acids (5-HT(1B/2ADelta44)). The equilibrium dissociation constant of the radioligand [(3)H]GR 125743 was similar for both chimera compared to the wild-type (wt) h 5-HT(1B) receptor upon transient expression in COS-7 cells. Ketanserin binding affinity was 21-fold increased from pK(i): 5.79 (wt h 5-HT(1B) receptor) to pK(i): 7.11 at the 5-HT(1B/2A) chimeric receptor, this latter value being close to that of the wt h 5-HT(1D) receptor (pK(i): 7.62). This enhanced ketanserin binding affinity was lost when the last 44 C-terminal amino acids of the 5-HT(2A) receptor were deleted in the chimera 5-HT(1B/2ADelta44) (pK(i): 5.80). The binding affinities of the 5-HT antagonists ritanserin, GR 125743, and SB-224289 were not modified at either chimeric 5-HT receptor. The agonists F 11356, 5-HT, zolmitriptan, and sumatriptan yielded slightly increased (2- to 6-fold) binding affinities at both chimera as compared to the wt h 5-HT(1B) receptor. The present data suggest a role for the C-terminal intracellular receptor domain in modifying ketanserin/5-HT(1B) receptor interactions.
- Published
- 2000
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40. F 11356, a novel 5-hydroxytryptamine (5-HT) derivative with potent, selective, and unique high intrinsic activity at 5-HT1B/1D receptors in models relevant to migraine.
- Author
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John GW, Pauwels PJ, Perez M, Halazy S, Le Grand B, Verscheure Y, Valentin JP, Palmier C, Wurch T, Chopin P, Marien M, Kleven MS, Koek W, Assie MB, Carilla-Durand E, Tarayre JP, and Colpaert FC
- Subjects
- Animals, Carotid Arteries drug effects, Carotid Arteries physiology, Colforsin pharmacology, Cyclic AMP pharmacology, Disease Models, Animal, Dogs, Dose-Response Relationship, Drug, Guanosine 5'-O-(3-Thiotriphosphate) pharmacology, Guinea Pigs, Heart drug effects, Heart physiology, Hemodynamics drug effects, Humans, Hypothermia chemically induced, In Vitro Techniques, Male, Muscle, Smooth, Vascular drug effects, Muscle, Smooth, Vascular physiology, Neurons drug effects, Rabbits, Radioligand Assay, Rats, Receptor, Serotonin, 5-HT1B, Receptor, Serotonin, 5-HT1D, Saphenous Vein drug effects, Swine, Trigeminal Ganglion cytology, Trigeminal Ganglion drug effects, Tryptamines, Migraine Disorders drug therapy, Nitriles pharmacology, Piperazines pharmacology, Receptors, Serotonin drug effects
- Abstract
F 11356 (4-[4-[2-(2-aminoethyl)-1H-indol-5-yloxyl]acetyl]piperazinyl-1-yl] ben zonitrile) was designed to take advantage of the superior potency and efficacy characteristics of 5-hydroxytryptamine (5-HT) compared with tryptamine at 5-HT1B/1D receptors. F 11356 has subnanomolar affinity for cloned human and nonhuman 5-HT1B and 5-HT1D receptors, and its affinity for 5-HT1A and other 5-HT receptors, including the 5-ht1F subtype, is 50-fold lower and micromolar, respectively. In C6 cells expressing human 5-HT1B or human 5-HT1D receptors, F 11356 was the most potent compound in inhibiting forskolin-induced cyclic AMP formation (pD2 = 8.9 and 9.6), and in contrast to tryptamine and derivatives, it produced maximal enhancement of [35S]guanosine-5'-O-(3-thio)triphosphate-specific binding equivalent to 5-HT. F 11356 was equipotent to 5-HT (pD2 = 7.1 versus 7.2) and more potent than tryptamine derivatives in contracting rabbit isolated saphenous vein. In isolated guinea pig trigeminal ganglion neurons, F 11356 was more potent (pD2 = 7.3 versus 6.7) and induced greater increases in outward hyperpolarizing Ca2+-dependent K+ current than sumatriptan. In anesthetized pigs, F 11356 elicited highly cranioselective, more potent (from 0.16 microgram/kg i.v.) and greater carotid vasoconstriction than tryptamine derivatives. Decreases in carotid blood flow were observed in conscious dogs from 0.63 mg/kg oral F 11356 in the absence of changes in heart rate or behavior. Oral activity was confirmed when hypothermic responses were elicited in guinea pigs (ED50 = 1.6 mg/kg), suggesting that F 11356 also accesses the brain. F 11356 thus is a selective, high-potency agonist at 5-HT1B/1D receptors, which distinguishes itself from tryptamine and derivatives in exerting high intrinsic activity at these receptors in vascular and neuronal models relevant to migraine.
- Published
- 1999
41. Multiple forms of arginase are differentially expressed from a single locus in Neurospora crassa.
- Author
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Marathe S, Yu YG, Turner GE, Palmier C, and Weiss RL
- Subjects
- Amino Acid Sequence, Animals, Base Sequence, Cloning, Molecular, DNA, Recombinant, Humans, Molecular Sequence Data, Mutagenesis, Site-Directed, Neurospora crassa enzymology, Polymorphism, Restriction Fragment Length, Sequence Homology, Amino Acid, Arginase genetics, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Fungal, Neurospora crassa genetics
- Abstract
The Neurospora crassa catabolic enzyme, arginase (L-arginine amidinohydrolase, EC 3.5.3.1), exists in multiple forms. Multiple forms of arginase are found in many vertebrates, but this is the only reported example in a microbial organism. The two major forms are structurally similar with subunit sizes of 36 and 41 kDa, respectively. The larger form is produced by mycelia growing in arginine-supplemented medium. Both forms are localized in the cytosol. The structural gene for arginase, aga, has been cloned and sequenced; it contains a 358-codon open reading frame with three in-frame ATGs at the amino terminus. Mutagenesis of these ATGs revealed that the first ATG initiates the 41-kDa protein and the third ATG initiates the 36-kDa protein. Mutation of the second ATG has no effect on translation. Northern analysis demonstrated that a 1.4-kilobase (kb) transcript is synthesized in minimal medium and both a 1.4- and 1.7-kb transcript are produced in arginine-supplemented medium. Primer extension identified the 5' ends of each transcript and demonstrated that the first and third ATG of the open reading frame are the initial AUGs of the 1.7- and 1. 4-kb mRNA, respectively. The results suggest that a basal promoter produces the 1.4-kb transcript and an arginine "activated" promoter is responsible for the 1.7-kb transcript. Tandem promoters are rare in eukaryotic organisms, and they often regulate developmental or tissue-specific gene expression. The possibility that arginase has a role in differentiation in N. crassa is being investigated.
- Published
- 1998
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42. F 11440, a potent, selective, high efficacy 5-HT1A receptor agonist with marked anxiolytic and antidepressant potential.
- Author
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Koek W, Patoiseau JF, Assié MB, Cosi C, Kleven MS, Dupont-Passelaigue E, Carilla-Durand E, Palmier C, Valentin JP, John G, Pauwels PJ, Tarayre JP, and Colpaert FC
- Subjects
- 8-Hydroxy-2-(di-n-propylamino)tetralin pharmacology, Adrenergic alpha-1 Receptor Antagonists, Animals, Colforsin pharmacology, Columbidae, Conflict, Psychological, Corticosterone metabolism, Cyclic AMP biosynthesis, Dopamine Antagonists pharmacology, HeLa Cells, Humans, Male, Microdialysis, Radioligand Assay, Rats, Rats, Sprague-Dawley, Receptors, Serotonin metabolism, Receptors, Serotonin, 5-HT1, Anti-Anxiety Agents pharmacology, Antidepressive Agents pharmacology, Pyrimidines pharmacology, Receptors, Serotonin drug effects, Serotonin Receptor Agonists pharmacology, Triazines pharmacology
- Abstract
F 11440 (4-methyl-2-[4-(4-(pyrimidin-2-yl)-piperazino)-butyl]-2H, 4H-1,2,4-triazin-3,5-dione) was the outcome of a research effort guided by the hypothesis that the magnitude of the intrinsic activity of agonists at 5-HT1A receptors determines the magnitude of their antidepressant and anxiolytic-like effects. The affinity of F 11440 for 5-HT1A binding sites (pKi, 8.33) was higher than that of buspirone (pKi, 7.50), and somewhat lower than that of flesinoxan (pKi, 8.91). In vivo, F 11440 was 4- to 20-fold more potent than flesinoxan, and 30- to 60-fold more potent than buspirone, in exerting 5-HT1A agonist activity at pre- and postsynaptic receptors in rats (measured by, for example, its ability to decrease hippocampal extracellular serotonin (5-HT) levels and to increase plasma corticosterone levels, respectively). F 11440 did not have detectable antidopaminergic activity (unlike buspirone, which inhibited all of the directly observable behavioral effects of methylphenidate in rats), showed no evidence of antihistaminergic activity (unlike flesinoxan, which protected against the effects of a histamine aerosol in guinea pigs), and had a 70-fold separation between its 5-HT1A agonist and alpha-1 adrenergic antagonist properties (measured as the ability to inhibit the methoxamineinduced increase in blood pressure in rats), unlike flesinoxan, which showed a <3-fold separation. In HeLa cells expressing human 5-HT1A receptors, F 11440 decreased the forskolin-induced increase in AMP, and, based on its maximal effect, was found to have an intrinsic activity of 1.0 relative to that of 5-HT, which was significantly higher than that of buspirone (0.49), ipsapirone (0.46) and flesinoxan (0.93). Consistent with the aforementioned hypothesis, F 11440 produced anxiolytic- and antidepressant-like effects in animal models (i.e., increased punished responding in a pigeon conflict procedure and decreased immobility in a rat forced swimming test, respectively) that were more substantial than those of buspirone, ipsapirone and flesinoxan. Thus, F 11440, shown here to be a potent, selective, high efficacy 5-HT1A receptor agonist, appears to have the potential to exert marked anxiolytic and antidepressant activity in humans.
- Published
- 1998
43. 5-(Sulfonyl)oxy-tryptamines and ethylamino side chain restricted derivatives. Structure-affinity relationships for h5-HT1B and h5-HT1D receptors.
- Author
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Barf T, Wikström H, Pauwels PJ, Palmier C, Tardif S, Lundmark M, and Sundell S
- Subjects
- Animals, COS Cells, Crystallography, X-Ray, HeLa Cells, Humans, Magnetic Resonance Spectroscopy, Mass Spectrometry, Protein Binding, Receptor, Serotonin, 5-HT1B, Receptor, Serotonin, 5-HT1D, Recombinant Proteins metabolism, Structure-Activity Relationship, Tryptamines metabolism, Receptors, Serotonin metabolism, Tryptamines chemistry, Tryptamines pharmacology
- Abstract
A number of sulfonic acid ester derivatives of serotonin (5-hydroxytryptamine; 5-HT; 1) were prepared and their affinities are compared to that of the reference compound 5-[[(trifluoromethyl)sulfonyl]oxy]-tryptamine (8b). The structure-affinity relationship (SAFIR) is discussed in terms of in vitro binding for cloned human h5-HT1A, h5-HT1B and h5-HT1D receptors. All tryptamine derivatives exhibited the best affinities for h5-HT1D receptors but still, these were comparatively lower than that of compound 8b. 5-Tosylated tryptamine 11b (Ki = 6 nM) and the sulfamate derivatives 13b and 14b (Ki = 7 and 11 nM, respectively) were found to have the highest affinities for the h5-HT1D receptor. Other tryptamine derivatives displayed moderate binding for h5-HT1A and h5-HT1B receptors, along with Ki values ranging from 14-20 nM for the h5-HT1D sites. In addition, the syntheses of two alkylamino side chain restricted derivatives are described. 3-Amino-6-[[(trifluoromethyl)sulfonyl]oxy]-1,2,3,4-tetrahydrocarbazol e 21, as well as 4-[5-[[(trifluoromethyl)sulfonyl]oxy]-1H-indol-3-yl]piperidines 24 and 25, induced a shift in selectivity in favor of the h5-HT1B receptor. The relatively longer distance between the basic amine and a hydrogen-bond accepting oxygen in 21, 24 and 25 as compared to the non-restricted tryptamines, is likely responsible for this observation.
- Published
- 1998
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44. Interaction of 5-HT1B/D ligands with recombinant h 5-HT1A receptors: intrinsic activity and modulation by G-protein activation state.
- Author
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Pauwels PJ, Palmier C, Dupuis DS, and Colpaert FC
- Subjects
- Cell Membrane drug effects, Cell Membrane metabolism, Dihydroergotamine pharmacology, Guanosine Diphosphate pharmacology, HeLa Cells, Humans, Lisuride pharmacology, Radioligand Assay, Recombinant Proteins metabolism, GTP-Binding Proteins metabolism, Neuroglia metabolism, Receptors, Serotonin metabolism, Serotonin Receptor Agonists pharmacology
- Abstract
Many 5-HT1B/D receptor ligands have affinity for 5-HT1A receptors. In the present study, the intrinsic activity of a series of 5-HT1B/D ligands was investigated at human 5-HT1A (h 5-HT1A) receptors by measuring G-protein activation in recombinant C6-glial and HeLa membranes, using agonist-stimulated [35S]GTPgammaS binding. In these two membrane preparations, the density of h 5-HT1A receptors (i.e., 246 to 320 fmol mg(-1) protein) and of their G-proteins, and the receptor: G-protein density ratio (0.08 to 0.18) appeared to be similar. It was found that: (i) the maximal [35S]GTPgammaS binding responses induced by the 5-HT1B/D receptor ligands in the HeLa preparation at 30 microM GDP were comparable to that of the native agonist 5-HT; (ii) as compared to 5-HT (1.00), similar potencies but lower maximal responses were observed in the C6-glial preparation at 0.3 microM GDP for zolmitriptan (0.89), dihydroergotamine (0.81), rizatriptan (0.71), CP122638 (0.69), naratriptan (0.60) and sumatriptan (0.53); and that (iii) maximal [35S]GTPgammaS binding responses induced by 5-HT1B/D ligands in the C6-glial preparation were either unaffected or significantly enhanced by increasing the GDP concentration from 0.3 to 30 microM and higher concentrations. These features differ from those observed with 5-HT1A receptor agonists; the latter display the same rank order of potency and efficacy in both membrane preparations, and increasing the amount of GDP with C6-glial membranes results in an attenuation of both the agonist's maximal effect and the apparent potency of partial agonists. The differential regulation of 5-HT1A and 5-HT1B/D agonist responses by GDP suggests that different G-protein subtypes are involved upon 5-HT1A receptor activation by 5-HT1A and 5-HT1B/D agonists.
- Published
- 1998
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45. Autoradiography of serotonin 5-HT1A receptor-activated G proteins in guinea pig brain sections by agonist-stimulated [35S]GTPgammaS binding.
- Author
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Dupuis DS, Palmier C, Colpaert FC, and Pauwels PJ
- Subjects
- 8-Hydroxy-2-(di-n-propylamino)tetralin pharmacology, Animals, Autoradiography, Guanosine 5'-O-(3-Thiotriphosphate) metabolism, Guinea Pigs, Hippocampus chemistry, Male, Oxadiazoles pharmacology, Piperazines pharmacology, Raphe Nuclei chemistry, Receptor, Serotonin, 5-HT1B, Receptors, Serotonin physiology, Receptors, Serotonin, 5-HT1, Septal Nuclei chemistry, Serotonin Receptor Agonists pharmacology, Sulfur Radioisotopes, Tryptamines pharmacology, Brain Chemistry, GTP-Binding Proteins analysis, GTP-Binding Proteins metabolism, Guanosine 5'-O-(3-Thiotriphosphate) pharmacology, Receptors, Serotonin analysis
- Abstract
G protein activation mediated by serotonin 5-HT1A and 5-HT(1B/D) receptors in guinea pig brain was investigated by using quantitative autoradiography of agonist-stimulated [35S]GTPgammaS binding to brain sections. [35S]GTPgammaS binding was stimulated by the mixed 5-HT1A/5-HT(1B/D) agonist L694247 in brain structures enriched in 5-HT1A binding sites, i.e., hippocampus (+140 +/- 14%), dorsal raphe (+70 +/- 8%), lateral septum (+52 +/- 12%), cingulate (+36 +/- 8%), and entorhinal cortex (+34 +/- 5%). L694247 caused little or no stimulation of [35S]GTPgammaS binding in brain regions with high densities of 5-HT(1B/D) binding sites (e.g., substantia nigra, striatum, central gray, and dorsal subiculum). The [35S]GTPgammaS binding response was antagonized by WAY100635 (10 microM) and methiothepin (10 microM). In contrast, the 5-HT1B inverse agonist SB224289 (10 microM) did not affect the L694247-mediated [35S]GTPgammaS binding response, and the mixed 5-HT(1B/D) antagonist GR127935 (10 microM) yielded a partial blockade. The distribution pattern of the [35S]GTPgammaS binding response and the antagonist profile suggest the L694247-mediated response in guinea pig brain to be mediated by 5-HT1A receptors. In addition to L694247, 8-hydroxy-2-(di-n-propylamino)tetralin, and flesinoxan also stimulated [35S]GTPgammaS binding; their maximal responses varied between 46 and 52% compared with L694247, irrespective of the brain structure being considered. Sumatriptan, rizatriptan, and zolmitriptan (10 microM) stimulated [35S]GTPgammaS binding in the hippocampus by 20-50%. Naratriptan, CP122638, and dihydroergotamine stimulated [35S]GTPgammaS binding to a similar level as L694247 in hippocampus, lateral septum, and dorsal raphe. It appears that under the present experimental conditions, G protein activation through 5-HT1A but not 5-HT(1B/D) receptors can be measured in guinea pig brain sections.
- Published
- 1998
- Full Text
- View/download PDF
46. Pharmacological analysis of G-protein activation mediated by guinea-pig recombinant 5-HT1B receptors in C6-glial cells: similarities with the human 5-HT1B receptor.
- Author
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Pauwels PJ, Wurch T, Palmier C, and Colpaert FC
- Subjects
- Amino Acid Sequence, Animals, Cell Line, Cell Membrane metabolism, Cloning, Molecular, Cyclic AMP metabolism, Guanosine 5'-O-(3-Thiotriphosphate) metabolism, Guinea Pigs, Humans, Molecular Sequence Data, Neuroglia drug effects, Polymerase Chain Reaction, RNA, Messenger biosynthesis, Rats, Receptors, Serotonin biosynthesis, Receptors, Serotonin genetics, GTP-Binding Proteins metabolism, Neuroglia metabolism, Receptors, Serotonin metabolism
- Abstract
1. The guinea-pig recombinant 5-hydroxytryptamine1B (gp 5-HT1B) receptor stably transfected in rat C6-glial cells was characterized by monitoring G-protein activation in a membrane preparation with agonist-stimulated [35S]-GTPgammaS binding. The intrinsic activity of 5-HT receptor ligands was compared with that determined previously at the human recombinant 5-HT1B (h 5-HT1B) receptor under similar experimental conditions. 2. Membrane preparations of C6-glial/gp 5-HT1B cells exhibited [3H]-5-carboxamidotryptamine (5-CT) and [3H]-N-[4-methoxy-3,4-methylpiperazin-1-yl) phenyl]-3-methyl-4-(4-pyridinyl)benzamide (GR 125743) binding sites with a pKd of 9.62 to 9.85 and a Bmax between 2.1 to 6.4 fmol mg(-1) protein. The binding affinities of a series of 5-HT receptor ligands determined with [3H]-5-CT and [3H]-GR 125743 were similar. Ligand affinities were comparable to and correlated (r2: 0.74, P<0.001) with those determined at the recombinant h 5-HT1B receptor. 3. [35S]-GTPgammaS binding to membrane preparations of C6-glial/gp 5-HT1B cells was stimulated by the 5-HT receptor agonists that were being investigated. The maximal responses of naratriptan, zolmitriptan, sumatriptan, N-methyl-3-[pyrrolidin-2(R)-ylmethyl]-1H-indol-5-ylmethyl sulphonamide (CP 122638), rizatriptan and dihydroergotamine were between 0.76 and 0.85 compared to 5-HT. The potency of these agonists showed a positive correlation (r2: 0.72, P=0.015) with their potency at the recombinant h 5-HT1B receptor. 1-naphthylpiperazine, (+/-)-cyanopindolol and (2'-methyl-4'-(5-methyl[1,2,4] oxadiazole-3-yl)biphenyl-4-carboxylic acid [4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amide (GR 127935) elicited an even smaller response (Emax: 0.32 to 0.63). 4. The ligands 1'-methyl-5-(2'-methyl-4'-(5-methyl-1,2,4-oxadiazole-3-yl) biphenyl-4-carbonyl)-2,3,6,7tetrahydrospiro [furo[2,3-f]indole-3-spiro-4'-piperidine] (SB224289), methiothepin and ritanserin displayed inhibition of basal [35S]-GTPgammaS binding at concentrations relevant to their binding affinity for the gp 5-HT1B receptor. Methiothepin and SB224289 behaved as competitive antagonists at gp 5-HT1B receptors; pA2 values were 9.74 and 8.73, respectively when 5-HT was used as an agonist. These estimates accorded with the potencies measured in antagonism of zolmitriptan-mediated inhibition of forskolin-stimulated cyclic AMP formation. Ketanserin acted as a weak antagonist (pK(B): 5.87) at gp 5-HT1B receptors. 5. In conclusion, the recombinant gp 5-HT1B receptor shares important pharmacological similarities with the recombinant h 5-HT1B receptor. The finding that negative activity occurs at these receptors further suggests that SB224289, methiothepin and ritanserin are likely to be inverse agonists.
- Published
- 1998
- Full Text
- View/download PDF
47. 5-HT1B receptor antagonist properties of novel arylpiperazide derivatives of 1-naphthylpiperazine.
- Author
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Jorand-Lebrun C, Pauwels PJ, Palmier C, Moret C, Chopin P, Perez M, Marien M, and Halazy S
- Subjects
- Animals, CHO Cells metabolism, CHO Cells ultrastructure, COS Cells metabolism, COS Cells ultrastructure, Cricetinae, Drug Design, Guinea Pigs, HeLa Cells, Humans, Kinetics, Piperazines metabolism, Rats, Receptor, Serotonin, 5-HT1B, Receptors, Serotonin metabolism, Serotonin Antagonists metabolism, Serotonin Receptor Agonists metabolism, Piperazines chemical synthesis, Piperazines pharmacology, Receptors, Serotonin drug effects, Serotonin Antagonists chemical synthesis, Serotonin Antagonists pharmacology, Serotonin Receptor Agonists chemical synthesis, Serotonin Receptor Agonists pharmacology
- Abstract
A new series of arylpiperazide derivatives of 1-naphthylpiperazine of general formula 4 has been prepared and evaluated as 5-HT1B antagonists. Binding experiments at cloned human 5-HT1A, 5-HT1B, and 5-HT1D receptors show that these derivatives are potent and selective ligands for 5-HT1B/1D subtypes with increased binding selectivity versus the 5-HT1A receptor when compared to 1-naphthylpiperazine (1-NP). Studies of inhibition of the forskolin-stimulated cAMP formation mediated by the human 5-HT1B receptor demonstrate that the nature of the arylpiperazide substituent modulates the intrinsic activity of these 1-NP derivatives. Among them, 2-[[8-(4-methylpiperazin-1-yl)naphthalen-2-yl]oxy] -1-(4-o-tolylpiperazin-1-yl)ethanone (4a) was identified as a potent neutral 5-HT1B antagonist able to antagonize the inhibition of 5-HT release induced by 5-CT (5-carbamoyltryptamine) in guinea pig hypothalamus slices. Moreover, 4a was found to potently antagonize the hypothermia induced by a selective 5-HT1B/1D agonist in vivo in the guinea pig following oral administration (ED50 = 0.13 mg/kg).
- Published
- 1997
- Full Text
- View/download PDF
48. Recombinant saphenous vein 5-HT1B receptors of the rabbit: comparative pharmacology with human 5-HT1B receptors.
- Author
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Wurch T, Palmier C, Colpaert FC, and Pauwels PJ
- Subjects
- Animals, Cell Line, Colforsin pharmacology, Cyclic AMP biosynthesis, Haplorhini, Humans, Polymerase Chain Reaction, Rabbits, Rats, Receptors, Serotonin biosynthesis, Receptors, Serotonin drug effects, Recombinant Proteins biosynthesis, Serotonin Antagonists pharmacology, Serotonin Receptor Agonists pharmacology, Transfection, Muscle, Smooth, Vascular metabolism, Receptors, Serotonin genetics, Saphenous Vein metabolism
- Abstract
1. The rabbit recombinant saphenous vein 5-hydroxytryptamine1B (r 5-HT1B) receptor stably transfected in rat C6-glial cells was characterized by measuring adenosine 3':5'-cyclic monophosphate (cycle AMP) formation upon exposure to various 5-HT receptor ligands. The effects of agonists and antagonists were compared with their effects determined previously at the human cloned 5-HT1B (h 5-HT1B) receptor under similar experimental conditions. 2. Intact C6-glial cells expressing rb HT1B receptors exhibited [3H]-5-carboxamidotryptamine (5-CT) binding sites with a Kd of 0.80 +/- 0.13 nM and a Bmax between 225 to 570 fmol mg-1 protein. The binding affinities of a series of 5-HT receptor ligands determined in a membrane preparation with [3H]-5-CT or [3H]-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3-methyl-4-(-4 -pyridyl) benzamide (GR 125,743) were similar. With the exception of ketanserin, ligand affinities were comparable to those determined at the clones h 5-HT1B receptor site. 3. rb 5-HT1B receptors were negatively coupled to cyclic AMP formation upon stimulation with 5-HT agonists. Of the several 5-HT agonists tested, 5-CT was the most potent, the potency rank order being: 5-CT > 5-HT > zolmitriptan > naratriptan > rizatriptan > sumatriptan > R (+)-8-(hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). The maximal responses of these agonists were similar to those induced by 5-HT. The potency of these agonists showed a positive correlation (r2 = 0.87; P < 0.002) with their potency at the cloned h 5-HT1B receptor subtype. 4. 2'-Methyl-4-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-carboxylic acid [4-methoxy-e-(4-methyl-piperazin-1-yl)-phenyl]-amide (GR 127,935), methiothepin and ketanserin each behaved as silent, competitive antagonists at rb 5HT1B receptors; pKB values were 8.41, 8.32 and 7.05, respectively when naratriptan was used as an agonist. These estimates accorded with their binding affinities and the potencies found on 5-HT and/or sumatriptan-mediated contraction of isolated rabbit saphenous vein segments. 5. In conclusion, the recombinant saphenous vein 5-HT1B receptor of the rabbit shares important pharmacological similarities with the cloned h 5-HT1B receptor. However, ketanserin is a more potent antagonist of rb 5-HT1B receptors.
- Published
- 1997
- Full Text
- View/download PDF
49. Sequence and functional analysis of cloned guinea pig and rat serotonin 5-HT1D receptors: common pharmacological features within the 5-HT1D receptor subfamily.
- Author
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Wurch T, Palmier C, Colpaert FC, and Pauwels PJ
- Subjects
- Amino Acid Sequence, Animals, COS Cells, Cyclic AMP antagonists & inhibitors, Cyclic AMP metabolism, Dogs, Humans, Ligands, Mice, Molecular Sequence Data, Rabbits, Guinea Pigs metabolism, Rats metabolism, Receptors, Serotonin genetics, Receptors, Serotonin metabolism
- Abstract
This study was undertaken to investigate the pharmacology of cloned guinea pig and rat 5-hydroxytryptamine (serotonin; 5-HT)1D receptor sites. Guinea pig, rat, and mouse 5-HT1D receptor genes were cloned, and their amino acid sequences were compared with those of the human, dog, and rabbit. The overall amino acid sequence identity between these 5-HT1D receptors is high and varies between 86 and 99%. The sequence homology is slightly more divergent (13-27%) in the N-terminal extracellular region of these 5-HT1D receptors. Guinea pig and rat 5-HT1D receptors, stably and separately expressed in rat C6 glial cells, are negatively coupled to cyclic AMP formation upon stimulation with agonists, as previously found for cloned human 5-HT1D receptor sites. The cyclic AMP data show some common pharmacological features for the 5-HT1D receptors of guinea pig, rat, and human: an almost similar rank order of potency for the investigated 5-HT1D receptor agonists, stereoselectivity for the binding affinity and agonist potency of R(+)-8-hydroxy-2-(di-n-propylamino)tetralin, and equal 5-HT1D receptor-mediated antagonist potency for methiothepin and the 5-HT2 receptor antagonists ritanserin and ketanserin. In conclusion, the pharmacology of the cloned 5-HT1D receptor subtype seems, unlike the 5-HT1B receptor subtype, conserved among various mammal species such as the human, guinea pig, and rat.
- Published
- 1997
- Full Text
- View/download PDF
50. Serotonin dimers: application of the bivalent ligand approach to the design of new potent and selective 5-HT(1B/1D) agonists.
- Author
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Halazy S, Perez M, Fourrier C, Pallard I, Pauwels PJ, Palmier C, John GW, Valentin JP, Bonnafous R, and Martinez J
- Subjects
- Animals, Biopolymers, Humans, Ligands, Magnetic Resonance Spectroscopy, Rabbits, Receptors, Serotonin metabolism, Recombinant Proteins metabolism, Serotonin Receptor Agonists metabolism, Serotonin Receptor Agonists pharmacology, Serotonin Receptor Agonists chemistry
- Abstract
A series of serotonin dimers of formula 4 in which two serotonin moeities are linked together through their 5-hydroxyl residue has been prepared and evaluated as 5-HT(1B/1D) receptor agonists. Binding experiments at cloned human 5-HT(1B), 5-HT(1D), and 5-HT(1A) receptors show that all of these dimers are very potent ligands at 5-HT(1B/1D) receptors with increased binding selectivity vs the 5-HT(1A) receptor when compared to serotonin. Studies of inhibition of the forskolin-stimulated c-AMP formation mediated by the human 5-HT(1B) receptor (formerly the 5-HT(1Dbeta) receptor) demonstrate that all of these serotonin dimers behave as full agonists. Among them, the piperazide derivatives of bis-serotonin, 4g,j, were also identified as very potent agonists in contracting the New Zealand white rabbit saphenous vein (pD2 = 7.6 in each case compared to 5.8 for sumatriptan). Results analysis supports the hypothesis that the important increase in potency of the serotonin dimers can be attributed to the presence of two serotonin pharmacophores in the same molecule, while the enhanced selectivity for 5-HT(1B/1D) receptor subtypes may be due to the position of the spacer attachment to serotonin.
- Published
- 1996
- Full Text
- View/download PDF
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