| SSR180711, a novel selective alpha7 nicotinic receptor partial agonist: (1) binding and functional profile. | |
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MedLine Citation:
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PMID: 17019409 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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In this paper, we report on the pharmacological and functional profile of SSR180711 (1,4-Diazabicyclo[3.2.2]nonane-4-carboxylic acid, 4-bromophenyl ester), a new selective alpha7 acetylcholine nicotinic receptor (n-AChRs) partial agonist. SSR180711 displays high affinity for rat and human alpha7 n-AChRs (K(i) of 22+/-4 and 14+/-1 nM, respectively). Ex vivo (3)[H]alpha-bungarotoxin binding experiments demonstrate that SSR180711 rapidly penetrates into the brain (ID(50)=8 mg/kg p.o.). In functional studies performed with human alpha7 n-AChRs expressed in Xenopus oocytes or GH4C1 cells, the compound shows partial agonist effects (intrinsic activity=51 and 36%, EC(50)=4.4 and 0.9 microM, respectively). In rat cultured hippocampal neurons, SSR180711 induced large GABA-mediated inhibitory postsynaptic currents and small alpha-bungarotoxin sensitive currents through the activation of presynaptic and somato-dendritic alpha7 n-AChRs, respectively. In mouse hippocampal slices, the compound increased the amplitude of both glutamatergic (EPSCs) and GABAergic (IPSCs) postsynaptic currents evoked in CA1 pyramidal cells. In rat and mouse hippocampal slices, a concentration of 0.3 muM of SSR180711 increased long-term potentiation (LTP) in the CA1 field. Null mutation of the alpha7 n-AChR gene totally abolished SSR180711-induced modulation of EPSCs, IPSCs and LTP in mice. Intravenous administration of SSR180711 strongly increased the firing rate of single ventral pallidum neurons, extracellularly recorded in anesthetized rats. In microdialysis experiments, administration of the compound (3-10 mg/kg i.p.) dose-dependently increased extracellular acetylcholine (ACh) levels in the hippocampus and prefrontal cortex of freely moving rats. Together, these results demonstrate that SSR180711 is a selective and partial agonist at human, rat and mouse alpha7 n-AChRs, increasing glutamatergic neurotransmission, ACh release and LTP in the hippocampus. |
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Authors:
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Bruno Biton; Olivier E Bergis; Frédéric Galli; Alain Nedelec; Alistair W Lochead; Samir Jegham; Danielle Godet; Christophe Lanneau; Raphaël Santamaria; Françoise Chesney; Jacques Léonardon; Patrick Granger; Marc W Debono; Georg A Bohme; Frédéric Sgard; François Besnard; David Graham; Annick Coste; André Oblin; Olivier Curet; Xavier Vigé; Corinne Voltz; Liliane Rouquier; Josiane Souilhac; Vincent Santucci; Christiane Gueudet; Dominique Françon; Régis Steinberg; Guy Griebel; Florence Oury-Donat; Pascal George; Patrick Avenet; Bernard Scatton |
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Publication Detail:
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Type: In Vitro; Journal Article Date: 2006-10-04 |
Journal Detail:
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Title: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology Volume: 32 ISSN: 0893-133X ISO Abbreviation: Neuropsychopharmacology Publication Date: 2007 Jan |
Date Detail:
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Created Date: 2006-12-14 Completed Date: 2007-02-09 Revised Date: 2011-05-18 |
Medline Journal Info:
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Nlm Unique ID: 8904907 Medline TA: Neuropsychopharmacology Country: United States |
Other Details:
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Languages: eng Pagination: 1-16 Citation Subset: IM |
Affiliation:
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Central Nervous System Research Department, Sanofi-Aventis, Bagneux, France. bruno.biton@sanofi-aventis.com |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Animals, Newborn Bicyclo Compounds, Heterocyclic / pharmacology Binding Sites / drug effects Cells, Cultured Dose-Response Relationship, Drug Drug Interactions Gene Expression / drug effects, physiology Hippocampus / cytology Humans Membrane Potentials / drug effects Mice Mice, Inbred C57BL Mice, Knockout Neurons / drug effects, physiology Nicotinic Agonists / chemistry, pharmacokinetics*, pharmacology* Nicotinic Antagonists / pharmacology Oocytes / physiology Patch-Clamp Techniques / methods Protein Subunits / drug effects, physiology Rats Rats, Sprague-Dawley Receptors, Nicotinic / deficiency, physiology* Synaptic Transmission / drug effects, physiology gamma-Aminobutyric Acid / pharmacology |
| Chemical | |
Reg. No./Substance:
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0/Bicyclo Compounds, Heterocyclic; 0/Nicotinic Agonists; 0/Nicotinic Antagonists; 0/Protein Subunits; 0/Receptors, Nicotinic; 0/SSR180711; 0/alpha7 nicotinic acetylcholine receptor; 56-12-2/gamma-Aminobutyric Acid |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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