SSR180711, a Novel Selective α7 Nicotinic Receptor Partial Agonist: (1) Binding and Functional Profile
| Autor: | Marc Williams Debono, Alistair Lochead, Dominique Françon, Annick Coste, Pascal George, Francoise Chesney, André Oblin, Raphaël Santamaria, Corinne Voltz, Patrick Granger, Danielle Godet, Olivier Bergis, Liliane Rouquier, Alain Nedelec, Georg Andrees Bohme, Bernard Scatton, Samir Jegham, Frederic Galli, Bruno Biton, Guy Griebel, Christiane Gueudet, Vincent Santucci, F. Oury-Donat, David I. Graham, Jacques Léonardon, François Besnard, Régis Steinberg, Frédéric Sgard, Josiane Souilhac, Olivier Curet, Xavier Vigé, Christophe Lanneau, Patrick Avenet |
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| Rok vydání: | 2006 |
| Předmět: |
Patch-Clamp Techniques
alpha7 Nicotinic Acetylcholine Receptor Gene Expression Nicotinic Antagonists In Vitro Techniques Receptors Nicotinic Neurotransmission Hippocampal formation Biology Inhibitory postsynaptic potential Hippocampus Synaptic Transmission Partial agonist Membrane Potentials Rats Sprague-Dawley Mice medicine Animals Humans Drug Interactions Nicotinic Agonists Cells Cultured gamma-Aminobutyric Acid Acetylcholine receptor Mice Knockout Neurons Pharmacology Binding Sites Dose-Response Relationship Drug Long-term potentiation Bridged Bicyclo Compounds Heterocyclic Rats Mice Inbred C57BL Protein Subunits Psychiatry and Mental health Nicotinic agonist Animals Newborn nervous system Oocytes Biophysics Neuroscience Acetylcholine medicine.drug |
| Zdroj: | Neuropsychopharmacology. 32:1-16 |
| ISSN: | 1740-634X 0893-133X |
| DOI: | 10.1038/sj.npp.1301189 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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