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Pharmacology and signaling properties of epidermal growth factor receptor isoforms studied by bioluminescence resonance energy transfer

We have developed a new assay for measuring epidermal growth factor receptor (EGFR) activation using the bioluminescence resonance energy transfer (BRET) technology, which directly measures the recruitment of signaling proteins to activated EGFR. Our results demonstrate that EGFR BRET assays precisely measure the pharmacology and signaling properties of EGFR expressed in human embryonic kidney 293

Novel potent and efficacious nonpeptidic urotensin II receptor agonists

Six different series of nonpeptidic urotensin II receptor agonists have been synthesized and evaluated for their agonistic activity in a cell-based assay (R-SAT). The compounds are ring-opened analogues of the isochromanone-based agonist AC-7954 with different functionalities constituting the linker between the two aromatic ring moieties. Several of the compounds are highly potent and efficacious,

Identification of novel subtype selective RAR agonists

Drugs targeting retinoid receptors have been developed to treat a variety of therapeutic indications, but their success has been limited in part due to lack of selectivity. A novel functional cell-based assay R-SAT™ was employed to screen a small molecule chemical library and identify a variety of novel RAR agonists with various subtype selectivities, including RARβ/γ and RARγ selective agonists.

Intrinsic efficacy of antipsychotics at human D2, D3, and D4 dopamine receptors : Identification of the clozapine metabolite N-desmethylclozapine as a D2/D3 partial agonist

Drugs that antagonize D2-like receptors are effective antipsychotics, but the debilitating movement disorder side effects associated with these drugs cannot be dissociated from dopamine receptor blockade. The "atypical" antipsychotics have a lower propensity to cause extrapyramidal symptoms (EPS), but the molecular basis for this is not fully understood nor is the impact of inverse agonism upon th

Solution-phase parallel Wittig olefination : Synthesis of substituted 1,2-diarylethanes

An efficient strategy for solution-phase parallel synthesis of substituted 1,2-diarylethanes is described. A stilbene library was initially generated by Wittig olefination utilizing amino-labeled phosphines. The stilbene analogues were obtained in high yields and excellent purities after solid-phase extraction. Subsequent reduction of the stilbene libraries simultaneously unmasked functional group

Isochromanone-based urotensin-II receptor agonists

A series of analogues of the selective non-peptide urotensin II (UII) receptor agonist 3-(4-chlorophenyl)-3-(2-dimethylaminoethyl)-isochroman-1-one (AC-7954, 1) was synthesized and evaluated for UII agonist activity using a functional cell-based assay. The introduction of a methyl group in the 4-position resulted in a complete loss of activity, whereas substituents in the aromatic rings were benef

The role of M1 muscarinic receptor agonism of N-desmethylclozapine in the unique clinical effects of clozapine

Rationale: Clozapine is a unique antipsychotic, with efficacy against positive symptoms in treatment-resistant schizophrenic patients, and the ability to improve cognition and treat the negative symptoms characteristic of this disease. Despite its unique clinical actions, no specific molecular mechanism responsible for these actions has yet been described. Objectives and methods: To comprehensivel

Multistep solution-phase parallel synthesis of spiperone analogues

A flexible, multistep parallel synthesis of spiperone analogues is described. A library of 4-substituted piperidines, assembled utilizing reductive amination and acylation protocols, was alkylated either homogeneously or heterogeneously, exploiting a product release only concept, to afford an oxa-series of spiperone analogues. Screening of the products at 5-HT2 and D2 receptors revealed 5-HT(2A) a

General combinatorial synthesis of tertiary amines on solid support. A novel conditional release strategy based on traceless linking at nitrogen

A novel solid phase synthesis of tertiary amines involving iodide-induced cleavage of the N-O bond of resin bound alkoxyammonium intermediates is described. The quaternary intermediates were assembled via sequential reductive aminations followed by alkylation. Cleavage from the solid support was induced by iodide ion or base, to afford the target tertiary amines in excellent purity.

Discovery of the first nonpeptide agonist of the GPR14/Urotensin-II receptor : 3-(4-Chlorophenyl)-3-(2-(dimethylamino)ethyl)isochroman-1-one (AC-7954)

A functional cell-based screen identified 3-(4-chlorophenyl)-3-(2-(dimethylamino)ethyl)isochroman-1-one hydrochloride (AC-7954, 1) as a nonpeptidic agonist of the urotensin-II receptor. Racemic 1 had an EC50 of 300 nM at the human UII receptor and was highly selective. Testing of the enantiopure (+)- and (-)-1 revealed that the UII receptor activity of racemic 1 resides primarily in (+)-1. Being a

Microwave-assisted solvent-free parallel synthesis of thioamides

Rapid parallel synthesis of thioamides is described. A library of amides, synthesised by mixing acyl chlorides and diamines, was transformed into the corresponding thioamides utilising Lawesson's reagent as the oxygen/sulphur exchange reagent. Purification by solid-phase extraction afforded the library members in adequate purities and yields. (C) 2000 Elsevier Science Ltd.

Beyond individuals - A Process of Routinizing Behaviors Through Entrepreneurial Learning : Insights from Technology-Based Ventures

The primary aim of this thesis is to develop a theoretical model that enhances our understanding of entrepreneurial learning as a process by which personalized streams of experience become routinized and embedded in venture-wide behaviors. The aim is realized by exploring entrepreneurial learning as an experiential multilevel process. This process begins with learning at the individual level, whic

Chelation-controlled regioselective endo cleavage and stereoselective C-1 alkylation of pentofuranosides

Combinations of Lewis acids and nucleophilic reagents trigger endo-opening of the furanoside ring of methyl furanosides 1, 10 and 13, resulting in the attachment of the nucleophilic group at C-1 of the carbohydrate. The stereoselectivity in the C-C bond-forming step is low for the 2-deoxyfuranosides but very high (dr 1:99) for the furanosides carrying a methoxy group in the 2-position when a combi

Endocyclic cleavage of glycosides. VI. Substituent effects of the alkylative endocyclic cleavage of glycosides

A number of pentopyranoside derivatives were treated with Me 3 Al in order to investigate the influence of structural parameters on the methyl group transfer in the endocyclic alkylative cleavage reaction of these substrates. A cyclic CH ··· O hydrogen bonded model is suggested as an intermediate, which is used to explain the stereoselectivities for different substrates. In several, cases the dia

Organotitanium-induced stereoselective alkylative endo-cleavage of benzyl pentopyranosides

The results presented are the first examples where organotitanium reagents induced alkylative endo-cleavage of carbohydrates. The best conditions for the alkylative transfer of a methyl group to benzyl 2-deoxy- 2-C-methyl-4-O-(tert-butyldimethylsilyl)-α-D-arabinopyranoside (1) were the application of one equivalent of AlMe3 followed by four equivalents of MeTiCl3 generated by mixing TiCl4 and ZnMe