1. ¹Central Nervous System Research Department, Sanofi-Aventis, Bagneux, France
2. ²Central Nervous System Research Department, Neurological Diseases, Sanofi-Aventis, Vitry sur Seine, France
3. ³Functional and Molecular Biology Department, Sanofi-Aventis, Rueil Malmaison, France
4. ⁴Central Nervous System Research Department, Sanofi-Aventis, Montpellier, France

Correspondence: Dr B Biton, CNS Research Department, Sanofi-Aventis, 31 avenue Paul Vaillant-Couturier, 92220 Bagneux, France, Tel: +33 1 45 36 22 85; Fax: +33 1 45 36 29 09; E-mail: bruno.biton@sanofi-aventis.com

Received 16 March 2006; Revised 7 June 2006; Accepted 20 June 2006; Published online 4 October 2006.

Abstract

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 7 acetylcholine nicotinic receptor (n-AChRs) partial agonist. SSR180711 displays high affinity for rat and human 7 n-AChRs (K_i of 224 and 141 nM, respectively). Ex vivo ³[H]-bungarotoxin binding experiments demonstrate that SSR180711 rapidly penetrates into the brain (ID₅₀=8 mg/kg p.o.). In functional studies performed with human 7 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 M, respectively). In rat cultured hippocampal neurons, SSR180711 induced large GABA-mediated inhibitory postsynaptic currents and small -bungarotoxin sensitive currents through the activation of presynaptic and somato-dendritic 7 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 M of SSR180711 increased long-term potentiation (LTP) in the CA1 field. Null mutation of the 7 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 7 n-AChRs, increasing glutamatergic neurotransmission, ACh release and LTP in the hippocampus.