SSR180711, a novel selective α7 nicotinic receptor partial agonist:: (I) binding and functional profile

In this paper, we report on the pharmacological and functional profile of SSR 180711 (1,4-Diazabicyclo[3.2.2]nonane-4-carboxylic acid, 4-bromophenyl ester), a new selective alpha 7 acetylcholine nicotinic receptor (n-AChRs) partial agonist. SSR 180711 displays high affinity for rat and human alpha 7 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 (ID50=8 mg/kg p.o.). In functional studies performed with human a7 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 mu M, respectively). In rat cultured hippocampal neurons, SSR180711 induced large GABA-mediated inhibitory postsynaptic currents and small x-bungarotoxin sensitive currents through the activation of presynaptic and somato-dendritic alpha 7 n-AChRs, respectively. In mouse hippocampal slices, the compound increased the amplitude of both glutamatergic (EPSCs) and GABAergic (IPSCs) postsynaptic currents evoked in CAI pyramidal cells. In rat and mouse hippocampal slices, a concentration of 0.3 mu M of SSR180711 increased long-term potentiation (LTP) in the CAI field. Null mutation of the alpha 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 alpha 7 n-AChRs, increasing glutamatergic neurotransmission, ACh release and LTP in the hippocampus.