Pimavanserin, a 5HT receptor inverse agonist, rapidly suppresses Aβ production and related pathology in a mouse model of Alzheimer's disease.

Amyloid-β (Aβ) peptide aggregation into soluble oligomers and insoluble plaques is a precipitating event in the pathogenesis of Alzheimer's disease (AD). Given that synaptic activity can regulate Aβ generation, we postulated that 5HT -Rs may regulate Aβ as well. We treated APP/PS1 transgenic mice with the selective 5HT inverse agonists M100907 or Pimavanserin systemically and measured brain interstitial fluid (ISF) Aβ levels in real-time using in vivo microdialysis.

Effect of escitalopram on Aβ levels and plaque load in an Alzheimer mouse model.

Background: Several neurotransmitter receptors activate signaling pathways that alter processing of the amyloid precursor protein (APP) into β-amyloid (Aβ). Serotonin signaling through a subset of serotonin receptors suppresses Aβ generation. We proposed that escitalopram, the most specific selective serotonin reuptake inhibitor (SSRI) that inhibits the serotonin transporter SERT, would suppress Aβ levels in mice.

Rapid in vivo measurement of β-amyloid reveals biphasic clearance kinetics in an Alzheimer's mouse model.

Findings from genetic, animal model, and human studies support the observation that accumulation of the β-amyloid (Aβ) peptide in the brain plays a central role in the pathogenic cascade of Alzheimer's disease (AD). Human studies suggest that one key factor leading to accumulation is a defect in brain Aβ clearance. We have developed a novel microimmunoelectrode (MIE) to study the kinetics of Aβ clearance using an electrochemical approach.

Highly efficient diastereoselective reduction of alpha-fluoroimines.

A highly selective reduction of alpha-fluoroimines to the corresponding beta-fluoroamines has been developed utilizing trichlorosilane as the reductant. The key aspect of this reaction is the ability of fluorine and nitrogen to activate organosilanes leading to high diastereoselectivity (>100:1) in the product distribution. This new method provides a new avenue for the diastereoselective synthesis of beta-fluorinated amines in good yields and selectivity.

Rate constants for peroxidation of polyunsaturated fatty acids and sterols in solution and in liposomes.

Rate constants for autoxidation propagation of several unsaturated lipids in benzene solution at 37 degrees C and in phosphatidylcholine liposomes were determined by a linoleate radical clock. This radical clock is based on competition between hydrogen atom abstraction by an intermediate peroxyl radical derived from linoleic acid that leads to a trans,cis-conjugated hydroxyoctadecadienoic product and beta-fragmentation of the same peroxyl that gives the trans,trans-product hydroxyoctadecadienoic acid. Rate constants determined by this approach in solution relative to linoleic acid (k(p) = 62 M(-1) s(-1)) were: arachidonic acid (k(p) = 197 +/- 13 M(-1) s(-1)), eicosapentaenoic acid (k(p) = 249 +/- 16 M(-1) s(-1)), docosahexaenoic acid (k(p) = 334 +/- 37 M(-1) s(-1)), cholesterol (k(p)= 11 +/- 2 M(-1) s(-1)), and 7-dehydrocholesterol (k(p)= 2260 +/- 40 M(-1) s(-1)).

In vivo and in vitro lipid peroxidation of arachidonate esters: the effect of fish oil omega-3 lipids on product distribution.

The effect of lipid composition on the distribution of free radical oxidation products derived from arachidonic acid (20:4) esters has been studied in vitro and in vivo. Pro-inflammatory prostaglandin (PG) F2-like compounds, termed F2-isoprostanes (IsoPs), are produced in vivo and in vitro by the free radical-catalyzed peroxidation of arachidonic acid. Controlled free radical oxidation of mixtures of fatty acid esters in vitro showed that the formation of IsoPs from arachidonate is dramatically influenced by the presence of other fatty acid esters in the reaction mixture.

Disposition of 9-nitrocamptothecin and its 9-aminocamptothecin metabolite in relation to ABC transporter genotypes.

Purpose: The source of the pharmacokinetic variability of 9-nitrocamptothecin (9NC) and its 9-aminocamptothecin (9AC) metabolite is unknown. ATP-binding cassette (ABC) transporters have been reported to modulate camptothecin analogues, are associated with camptothecin resistance, and might also affect 9NC and 9AC pharmacokinetics. The aim of this study was to evaluate the functional consequence of known single nucleotide polymorphisms in the transporter genes ABCB1, ABCC2, and ABCG2 on the pharmacokinetic disposition of 9NC and 9AC.

Chelation-controlled diastereoselective reduction of alpha-fluoroketones.

The effect of Ti-based Lewis acids on the reduction of alpha-fluoropropiophenone was examined to determine whether chelation control could be used to direct the diastereoselectivity of conversion to an alpha-fluoro alcohol. Pretreatment of alpha-fluoropropiophenone with TiCl4 followed by reduction with LiBH4 in diethyl ether or methylene chloride provided the syn diastereomer predominantly, while use of Ti(OiPr)4 under identical conditions provided the anti diastereomer as the major product. The products are consistent with a chelation-controlled mechanistic pathway in the former reduction and a nonchelation pathway in the latter case.

Reduction of beta-hydroxyketones by SmI2/H2O/Et3N.

Reduction of a series of beta-hydroxyketones by SmI2/H2O/Et3N provided 1,3-diols in quantitative yields. The reactions were exceedingly clean with no byproduct formation, negating the need for further purification. Most reactions provided moderate to excellent diastereoselectivity with syn-diols as the major isomer in most instances.

Solvent-dependent diastereoselectivities in reductions of beta-hydroxyketones by SmI2.

The reductions of a series of beta-hydroxyketones by SmI(2) were examined in THF, DME, and CH(3)CN using methanol as a proton source. Reductions in THF and DME typically lead to the syn diastereomer with DME providing higher diastereoselectivities. Reductions in CH(3)CN provided the anti diastereomer predominantly.