Utilisation d'acides amines pour la synthese enantiospecifique d'alcaloiedes indoliques, pyrrolidiniques et piperidiniques

SIGLECNRS T Bordereau / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Pilot Scale Process Development of SL65.0102-10, an <i>N</i>‑Diazabicyclo[2.2.2]-octylmethyl Benzamide

The process development and improvements for route selection, adapted to large scale for the pilot-scale preparation of SL65.0102-10, an <i>N</i>-diazabicyclo­[2.2.2]-octylmethyl benzamide, a 5-HT₃ and 5-HT₄ receptor active ligand for the treatment of neurological disorders such as cognition impairment, are described in this article. Notable steps and enhancements are compared to the original route, including the improvement of a chiral epoxide synthesis by shortening the number of chemical steps, the deprotection of a quaternary ammonium salt, and the redesign of the final amidification coupling to avoid chromatography

Pilot Scale Process Development of SL65.0102-10, an <i>N</i>‑Diazabicyclo[2.2.2]-octylmethyl Benzamide

The process development and improvements for route selection, adapted to large scale for the pilot-scale preparation of SL65.0102-10, an <i>N</i>-diazabicyclo­[2.2.2]-octylmethyl benzamide, a 5-HT₃ and 5-HT₄ receptor active ligand for the treatment of neurological disorders such as cognition impairment, are described in this article. Notable steps and enhancements are compared to the original route, including the improvement of a chiral epoxide synthesis by shortening the number of chemical steps, the deprotection of a quaternary ammonium salt, and the redesign of the final amidification coupling to avoid chromatography

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

International audienceIn 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