Metalation/SRN1 coupling in heterocyclic synthesis. A convenient methodology for ring functionalization

International audienc

Synthesis of ortho -substituted aminopyridines. Metalation of pivaloylamino derivatives

International audienc

A new synthetic approach to biaryls of the rhazinilam type. Application to synthesis of three novel phenylpyridine-carbamate analogues.

International audienc

Expression of tyrosine hydroxylase and vasopressin in magnocellular neurons of salt-loaded aged rats

Tyrosine hydroxylase (TH) is expressed in catecholaminergic neurons. However, under certain conditions it is also ectopically expressed in magnocellular neurons of the hypothalamus. To test the hypothesis that this expression of TH is related to the cellular activation of these neurons and/or to the vasopressin (VP) expression, we studied the expression of both TH and VP in control and salt-loaded aged rats. Our results demonstrate that aged rats show a marked TH expression in VP cells which is further increased by osmotic stimulation in the absence of increase in VP synthesis in the supraoptic nucleus. The presence of TH-immunopositive dendritic swellings in the ventral part of this nucleus reveals the high state of plasticity of these neurons. Furthermore, the lack of several actors of catecholamine biosynthesis in these neurons suggests a different role for TH. This study further demonstrates an ectopic expression of TH in hypothalamic neurons of aged rats and a TH expression linked to the activation of VP neurons but unrelated to VP synthesis. Microsc. Res, Tech. 56:81-91, 2002. (C) 2002 Wiley-Liss, Inc

In vitro characterization of novel peptides inhibitors of endomorphin-degrading enzymes in the rat brain.

International audienc

Dihydroquinoline derivatives as redox chemical delivery systems (CDS) or “bio-oxidisable” prodrugs for brain delivery of acetylcholinesterase inhibitors: design, synthesis, [11C]radiosynthesis and biological evaluation

LDM TEPNational audienc

Dihydroquinoline Carbamate Derivatives as "Bio-oxidizable" Prodrugs for Brain Delivery of Acetylcholinesterase Inhibitors: [¹¹C] Radiosynthesis and Biological Evaluation

LDM TEP COLLInternational audienceWith the aim of improving the efficiency of marketed acetylcholinesterase (AChE) inhibitors in the symptomatic treatment of Alzheimer’s disease, plagued by adverse effects arising from peripheral cholinergic activation, this work reports a biological evaluation of new central AChE inhibitors based on an original “bio-oxidizable” prodrug strategy. After peripheral injection of the prodrug (1a) [IC50 > 1 mM (hAChE)] in mice, monitoring markers of central and peripheral cholinergic activation provided in vivo proof-of-concept for brain delivery of the drug (2a) [IC50 = 20 nM (hAChE)] through central redox activation of (1a). Interestingly, peripheral cholinergic activation has been shown to be limited in time, likely due to the presence of a permanent positive charge in (2a) promoting rapid elimination of the AChE inhibitor from the circulation of mice. To support these assumptions, the radiosynthesis with carbon-11 of prodrug 1a was developed for additional ex vivo studies in rats. Whole-body biodistribution of radioactivity revealed high accumulation in excretory organs along with moderate but rapid brain uptake. Radio-HPLC analyses of brain samples confirm rapid CNS penetration of [11C] (1a), while identification of [11C] (2a) and [11C] (3a) both accounts for central redox activation of (1a) and pseudoirreversible inhibition of AChE, respectively. Finally, Caco-2 permeability assays predicted metabolite (3a) as a substrate for efflux transporters (P-gp inter alia), suggesting that metabolite (3a) might possibly be actively transported out of the brain. Overall, a large body of evidence from in vivo and ex vivo studies on small animals has been collected to validate this “bio-oxidizable” prodrug approach, emerging as a very promising strategy in the rational design of selective central AChE inhibitors