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Article Dans Une Revue Neuropsychopharmacology Année : 2006

SSR180711, a novel selective alpha 7 nicotinic receptor partial agonist: (I) binding and functional profile

Bruno Biton
  • Fonction : Auteur
Alain Nedelec
  • Fonction : Auteur
Samir Jegham
  • Fonction : Auteur
David Graham
  • Fonction : Auteur
Annick Coste
  • Fonction : Auteur
André Oblin
  • Fonction : Auteur
Olivier Curet
  • Fonction : Auteur
Xavier Vige
  • Fonction : Auteur
Corinne Voltz
  • Fonction : Auteur
Guy Griebel
  • Fonction : Auteur
Pascal George
  • Fonction : Auteur

Résumé

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 α7 acetylcholine nicotinic receptor (n-AChRs) partial agonist. SSR180711 displays high affinity for rat and human α7 n-AChRs (Ki of 22±4 and 14±1 nM, respectively). Ex vivo 3[H]α-bungarotoxin binding experiments demonstrate that SSR180711 rapidly penetrates into the brain (ID50=8 mg/kg p.o.). In functional studies performed with human α7 n-AChRs expressed in Xenopus oocytes or GH4C1 cells, the compound shows partial agonist effects (intrinsic activity=51 and 36%, EC50=4.4 and 0.9 μM, respectively). In rat cultured hippocampal neurons, SSR180711 induced large GABA-mediated inhibitory postsynaptic currents and small α-bungarotoxin sensitive currents through the activation of presynaptic and somato-dendritic α7 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 μM of SSR180711 increased long-term potentiation (LTP) in the CA1 field. Null mutation of the α7 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 α7 n-AChRs, increasing glutamatergic neurotransmission, ACh release and LTP in the hippocampus.

Dates et versions

hal-04562615 , version 1 (29-04-2024)

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Citer

Bruno Biton, Olivier E. Bergis, Frédéric Galli, Alain Nedelec, Alistair W. Lochead, et al.. SSR180711, a novel selective alpha 7 nicotinic receptor partial agonist: (I) binding and functional profile. Neuropsychopharmacology, 2006, Neuropsychopharmacology, 32, pp.1-16. ⟨10.1038/sj.npp.1301189⟩. ⟨hal-04562615⟩
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