Anionic and zwitterionic copper(I) complexes incorporating an anionic N-heterocyclic carbene decorated with a malonate backbone: synthesis, structure and catalytic applications.

The anionic malonate-derived N-heterocyclic carbenes (maloNHCs) react cleanly and rapidly with copper chloride to generate the anionic complexes of type [(maloNHC)CuCl]·Li, which crystallize in the solid state either in an oligomeric trimer arrangement or in polymeric helixes depending on the substitution pattern and the solvent. Ten zwitterionic heteroleptic Cu(I) complexes combining the anionic maloNHC and a neutral imidazol-2-ylidene are also obtained in a very selective manner and fully characterized. Whereas the anionic complexes are relatively active catalysts for the hydrosilylation of carbonyl compounds, the zwitterionic complexes reveal to be efficient and extremely robust pre-catalysts for the intramolecular cyclopropanation reaction of a diazo ester and outperform the corresponding cationic Cu(i) complexes with classical imidazol-2-ylidenes.

Radiosynthesis and preclinical evaluation of 18F-F13714 as a fluorinated 5-HT1A receptor agonist radioligand for PET neuroimaging.

Unlabelled: PET brain imaging of the serotonin 1A (5-hydroxytryptamine 1A [5-HT(1A)]) receptor has been widely used in clinical studies. Currently, only a few well-validated radiolabeled antagonist tracers are available for in vivo imaging of this central receptor. 5-HT(1A) receptors exist in high- and low-affinity states, depending on their coupling to G proteins.

Rigid analogues of the α2-adrenergic blocker atipamezole: small changes, big consequences.

We report the discovery of a new family of α(2) adrenergic receptor antagonists derived from atipamezole. Affinities of the compounds at human α(2) and α(1b) receptors as well as their functional activities at hα(2A) receptors were determined in competition binding and G-protein activation assays, respectively. Central α(2) antagonist activities were confirmed in mice after oral administration.

F15599, a preferential post-synaptic 5-HT1A receptor agonist: activity in models of cognition in comparison with reference 5-HT1A receptor agonists.

We assessed the activity of F15599, a selective and high efficacy 5-HT(1A) agonist that preferentially activates post- versus pre-synaptic receptors, in rat cognition/memory models. F15599 (0.16 mg/kg i.

F15599, a highly selective post-synaptic 5-HT(1A) receptor agonist: in-vivo profile in behavioural models of antidepressant and serotonergic activity.

F15599 is a novel agonist with high selectivity and efficacy at serotonin 5-HT(1A) receptors (5-HT(1A)Rs). In signal transduction, electrophysiological and neurochemical tests, F15599 preferentially activates post-synaptic 5-HT(1A)Rs in rat frontal cortex. Such a profile may translate to an improved profile of therapeutic activity for mood disorders.

[18F]F15599, a novel 5-HT1A receptor agonist, as a radioligand for PET neuroimaging.

Purpose: The serotonin-1A (5-HT(1A)) receptor is implicated in the pathophysiology of major neuropsychiatric disorders. Thus, the functional imaging of 5-HT(1A) receptors by positron emission tomography (PET) may contribute to the understanding of its role in those pathologies and their therapeutics. These receptors exist in high- and low-affinity states and it is proposed that agonists bind preferentially to the high-affinity state of the receptor and therefore could provide a measure of the functional 5-HT(1A) receptors.

Cellular BRET assay suggests a conformational rearrangement of preformed TrkB/Shc complexes following BDNF-dependent activation.

We developed a cellular Bioluminescent Resonance Energy Transfer (BRET) assay based on the interaction of TrkB fused to Renilla luciferase with the intracellular adaptor protein Shc fused to Enhanced Yellow Fluorescent Protein (EYFP). The TrkB agonist Brain Derived Neurotrophic Factor (BDNF) induced a maximum BRET signal as of 10 min with an EC(50) value of 1.4 nM, similar to the other endogenous agonists NT-3 and NT-4/5, 1.

Myocardial protection by F 15845, a persistent sodium current blocker, in an ischemia-reperfusion model in the pig.

The specific persistent sodium current blocker F 15845 was tested in two myocardial ischemia-reperfusion models in the pig in order to evaluate its cardioprotective effects. In the first protocol, the left circumflex coronary artery was ligated for 60-min and then reperfused for 48-h. F 15845 (2.

3-(R)-[3-(2-methoxyphenylthio-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine bromhydrate (F 15845) prevents ischemia-induced heart remodeling by reduction of the intracellular Na+ overload.

The present study investigates whether 3-(R)-[3-(2-methoxyphenylthio-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine bromhydrate (F 15845), a new, persistent sodium current blocker, can reduce the ischemic Na(+) accumulation and exert short- and long-term cardioprotection after myocardial infarction. First, F 15845 concentration-dependently reduced veratrine-induced diastolic contracture (IC(50) = 0.14 microM) in isolated atria.

Na+ currents in cardioprotection: better to be late.

We report the discovery of a selective, potent inhibitor of the late current mediated by the cardiac isoform of the sodium channel (Na(V)1.5). The compound, 3,4-dihydro-N-[(2S)-3-[(2-hydroxy-3-methylphenyl)thio]-2-methylpropyl]-2H-(3R)-1,5-benzoxathiepin-3-amine (2d) (F 15741), blocks the late component of the Na(+) currents and greatly reduces veratridine- or ischemia-induced contracture in isolated tissue and whole heart.

Cholecystocholedocholithiasis: a case-control study comparing the short- and long-term outcomes for a "laparoscopy-first" attitude with the outcome for sequential treatment (systematic endoscopic sphincterotomy followed by laparoscopic cholecystectomy).

Background: No unanimous consensus has been achieved regarding the ideal management of cholecystocholedocholithiasis. The treatment of gallbladder and common bile duct (CBD) stones may be achieved currently according to a two-step-protocol (endoscopic sphincterotomy associated with laparoscopic cholecystectomy) or by a one-step laparoscopic procedure, including exploration of the CBD and cholecystectomy. Endoscopic sphincterotomy is reported to have considerable morbidity/mortality and CBD stone recurrence rates, whereas laparoscopic CBD clearance is a demanding procedure, which to date has not spread beyond specialized environments.

Synthetic studies on cyclobuta[a]indanes: stereocontrolled access to C9-substituted derivatives.

We report the preparation of novel ethyl cyclobuta[a]indane derivatives of pharmacological interest. The synthesis of compounds 5 was used as a model to study stereocontrolled access to C9-substituted cyclobutane from the corresponding cyclobutanone 1. Progress was made on two complementary aspects: (1) catalytic hydrogenation from the appropriate cyclobutene precursors; and (2) delivery of the C9 substituent through an intramolecular process.

Sodium late current blockers in ischemia reperfusion: is the bullet magic?

We describe the discovery of the first selective, potent, and voltage-dependent inhibitor of the late current mediated by the cardiac sodium channel Na V1.5. The compound 3,4-dihydro- N-[(2 S)-3-[(2-methoxyphenyl)thio]-2-methylpropyl]-2 H-(3 R)-1,5-benzoxathiepin-3-amine, 2a (F 15845), was identified from a novel family of 3-amino-1,5-benzoxathiepine derivatives.

High-efficacy 5-HT1A agonists for antidepressant treatment: a renewed opportunity.

We report the discovery of novel 5-HT1A receptor agonists and describe the process that led to the antidepressant candidate 9 (F 15599). 9 has nanomolar affinity for 5-HT1A binding sites and is over 1000-fold selective with respect to the other 5-HT1 receptor subtypes, 5-HT2-7 receptor families, and also numerous GPCRs, transporters, ion channels, and enzymes. In a cellular model of signal transduction, 9 activates h5-HT1A receptors with an efficacy superior to that of the prototypical 5-HT1A agonist (+/-)-8-OH-DPAT and comparators undergoing clinical trials.

Towards a new generation of potential antipsychotic agents combining D2 and 5-HT1A receptor activities.

We report the discovery and the synthesis of novel, potential antipsychotic compounds combining potent dopamine D2 receptor antagonist and serotonin 5-HT1A receptor agonist properties in the same molecule. We describe the structure-activity relationship that lead us to the promising derivative: N-[(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)ethyl]-3-(cyclopent-1-enyl)-benzylamine 16. The latter has high affinity for D2 and 5-HT1A receptors, whereas it possesses only a weak affinity for 5-HT2A sites.

Agonist specific L-type Ca(2+)-current stimulation in ventricular myocytes by a novel steroid-like compound.

In cardiac muscle the amplitude of Ca(2+) transients can be increased by enhancing Ca(2+) influx. Among the processes leading to increased Ca(2+) influx, agonists of the L-type Ca(2+)-channel can play an important role. Known pharmacological Ca(2+)-channel agonists act on different binding sites on the channel protein, which may lead not only to enhanced peak currents, but also to distinct changes in other biophysical characteristics of the current.

A novel steroid-like compound F90927 exerting positive-inotropic effects in cardiac muscle.

Here we report a novel steroid-like compound F90363, exhibiting positive inotropy in vivo and in vitro in various cardiac muscle preparations. F90363 is a racemic mixture composed of the stereoisomers (-)-F90926 and (+)-F90927. Only F90927 exerted positive inotropy, while F90926 induced a weak negative inotropy, but only at concentrations 10(3) times higher than F90927 and most likely resulting from an unspecific interaction.

KC 12291: an atypical sodium channel blocker with myocardial antiischemic properties.

KC 12291 was designed as a voltage-gated sodium channel (VGSC) blocker with cardioprotective properties. KC 12291 has moderate inhibitory effects on peak (or rapid) Na+ current, and markedly reduces sustained (or slowly or non-inactivating) Na+ current. This distinguishes KC 12291 from conventional VGSC blockers such as local anesthetics or antiarrhythmics, which have little or no cardioprotective properties.