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Agonist Ligands (agonist + ligand)

Distribution by Scientific Domains

Medical Sciences	80%

Selected Abstracts

Synthesis of (R)-(,)-2-Fluoronorapomorphine , A Precursor for the Synthesis of (R)-(,)-2-Fluoro- N -[11C]propylnorapomorphine for Evaluation as a Dopamine D2 Agonist Ligand for PET Investigations

EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 20 2005
Kåre Søndergaard
Abstract 2-Fluoronorapomorphine, the PET labelling precursor to 2-fluoro- N -[11C]propylnorapomorphine, was prepared in 13 steps from codeine in a total yield of 10,%. Codeine was converted in four steps into N -benzylnorcodeine which was oxidised by using the Swern protocol. Subsequent acid-catalysed rearrangement afforded N -benzylnormorphothebaine which was selectively triflylated at the 2-position and pivaloylated at the 11-position. The triflate underwent palladium-catalysed amination with benzophenone imine. Amination conditions required sequential base addition to give substantial conversion of the triflate to the corresponding N -substituted benzophenone imine. After acidic hydrolysis the resulting aniline was transformed into the 2-fluoro compound via the Balz,Schiemann reaction. Hydrogenolysis of the N -benzyl group followed by deprotection of the catechol moiety using BBr3 provided 2-fluoronorapomorphine. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005) [source]

Efficient help for autoreactive B-cell activation requires CD4+ T-cell recognition of an agonist peptide at the effector stage

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 9 2009
Brian D. Hondowicz
Abstract T-cell recognition of peptide/MHC complexes is flexible and can lead to differential activation, but how interactions with agonist (full activation) or partial agonist (suboptimal activation) peptides can shape immune responses in vivo is not well characterized. We investigated the effect of stimulation by agonist or partial agonist ligands during initial CD4+ T-cell priming, and subsequent T-B-cell cognate interactions, on antibody production by anti-chromatin B cells. We found that autoantibody production required TCR recognition of an agonist peptide at the effector stage of B-cell activation. However, interaction with a weak agonist ligand at this effector stage failed to promote efficient autoantibody production, even if the CD4+ T cells were fully primed by an agonist peptide. These studies suggest that the reactivity of the TCR for a target self-peptide during CD4+ T-B-cell interaction can be a critical determinant in restraining anti-chromatin autoantibody production. [source]

DNA methylation controls Foxp3 gene expression

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 6 2008
Julia
Abstract Compelling evidence suggests that Foxp3-expressing CD25+CD4+ regulatory T cells (Treg) are generated within the thymus as a separate lineage. However, Foxp3+CD4+ Treg can also be generated de novo in a TGF-,-dependent process from naive T cells by TCR triggering. Recently, we have shown that naturally occurring, but not in vitro TGF-,-induced Foxp3+ Treg display stable Foxp3 expression that was associated with selective demethylation of an evolutionarily conserved element within the Foxp3 locus named TSDR (Treg-specific demethylated region). Here, we report that inhibition of DNA methylation by azacytidine, even in absence of exogenous TGF-,, not only promoted de novo induction of Foxp3 expression during priming, but also conferred stability of Foxp3 expression upon restimulation. Most notably, such stable Foxp3 expression was found only for cells displaying enhanced TSDR demethylation. In contrast, in vitro TSDR methylation diminished its transcriptional activity. Foxp3+ Treg generated in vivo by DEC-205-mediated targeting of agonist ligands to dendritic cells showed long-term survival in the absence of the inducing antigen and exhibited efficient TSDR demethylation. Together, our data suggest that TSDR is an important methylation-sensitive element regulating Foxp3 expression and demonstrate that epigenetic imprinting in this region is critical for establishment of a stable Treg lineage. Supporting Information for this article is available at www.wiley-vch.de/contents/jc_2040/2008/38105_s.pdf [source]

Suboptimal engagement of the T-cell receptor by a variety of peptide,MHC ligands triggers T-cell anergy

IMMUNOLOGY, Issue 1 2010
Scheherazade Sadegh-Nasseri
Summary T cells recognize antigen via the T-cell receptor (TCR) and produce a spectrum of responses that range from activation to anergy or cell death. The variety of outcomes may be dictated by the strength of the signals transmitted upon cognate recognition of the TCR. The physiological outcome of TCR engagement is determined by several factors, including the avidity of the ligand for TCR, the duration of engagement, and the presence and nature of accessory molecules present on antigen-presenting cells (APCs). In this review, we discuss a model of anergy induced by presentation of low densities of peptide,major histocompatibility complex (MHC) ligand in CD4+ T cells and compare it to anergy induced by altered peptide ligands in an effort to identify a unifying mechanism. We suggest that altered peptide ligand (APL) and low densities of agonist ligands induce anergy by engaging less than optimal numbers of TCRs. The physiological impacts of anergy in memory CD4+ T cells are discussed. [source]