Potent Ligands (potent + ligand)

Distribution by Scientific Domains

Selected Abstracts

Synthesis and Hormonal Activity of the (25S)-Cholesten-26-oic Acids , Potent Ligands for the DAF-12 Receptor in Caenorhabditis elegans

René Martin
Abstract Using a highly stereoselective Evans aldol reaction for the introduction of the stereogenic center at C-25, we describe an efficient synthesis of the orthogonally diprotected (25S)-26-hydroxycholesterol 11. In a few synthetic steps, this crucial intermediate 11 has been converted into the four (25S)-cholesten-26-oic acids 1,4, which have been obtained in 12,15 steps and 19,53,% overall yield based on commercially available 3,-hydroxychol-5-en-24-oic acid (5). Our biological studies of the compounds 1,4 reveal that (25S)-,7 -dafachronic acid (1) represents the most active steroidal ligand for the hormonal receptor DAF-12 in Caenorhabditis elegans. Moreover, the saturated (25S)-dafachronic acid (3) represents a new ligand for this receptor and the (25S)-steroidal acids are more active as compared to their corresponding (25R)-counterparts.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009) [source]

Synthesis and Pharmacological Evaluation of 8- and 9-Substituted Benzolactam-V8 Derivatives as Potent Ligands for Protein Kinase,C, a Therapeutic Target for Alzheimer's Disease

CHEMMEDCHEM, Issue 3 2006
Abstract A central element in the pathophysiology of Alzheimer's disease (AD) is the formation of amyloid plaques, which result from abnormal processing of the amyloid precursor protein (APP). The processing of APP is largely provided by three key enzymes, namely the ,-, ,-, and ,-secretases. As the latter two contribute to the formation of neurotoxic A, fragments while ,-secretase does not, a decrease in the amyloidogenic products can be brought about either by inhibition of the ,- and ,-secretases or through the activation of ,-secretase. It is now known that the activation of protein kinase,C (PKC) enhances ,-secretase activity and therefore represents a possible target for the development of agents urgently needed for the treatment of this devastating neurodegenerative disorder. In the present study, new benzolactam-V8-based PKC activators were synthesized and tested for their binding affinity toward PKC,. All compounds tested showed binding values in the nanomolar concentration range. In accordance with previous publications, 9-substitution dramatically increased PKC binding affinity in comparison with the corresponding 8-substituted analogues. In addition to the location of the side chain on the aromatic ring, the binding affinities of these benzolactams were found to depend on the orientation, length, and electronic properties of this appendage. An interesting decrease in binding affinity was found for the 9-thienyl analogue 13, suggesting adverse electronic interactions of the sulfur atom with PKC or parts of the cellular membrane. [source]

Enantiomers of 2-[(Acylamino)ethyl]-1,4-benzodiazepines, Potent ligands of ,-opioid receptor: Chiral chromatographic resolution, configurational assignment, and biological activity

CHIRALITY, Issue 9 2001
O. Azzolina
Abstract Compounds 2a and 3a,e are racemic 2-[(acylamino)ethyl]-1,4-benzodiazepines, tifluadom analogs, with high affinity and selectivity towards the ,-opioid receptor. We describe the enantiomeric separation of all compounds through liquid chromatography with chiral stationary phases, as well as the resolution of the enantiomers of the most interesting compounds, 2a and 3a, by the semipreparative column Chiralpak AD. The configuration of the resolved enantiomers was investigated: the comparative study of CD and 1H NMR spectra shows that compounds (,)- 2a and (,)- 3a have the same absolute configuration of (+)-(S)-tifluadom. A study on the stereoselective interaction with opiate receptors is reported. Chirality 13:606,612, 2001. © 2001 Wiley-Liss, Inc. [source]

Small potent ligands to the insulin-regulated aminopeptidase (IRAP)/AT4 receptor

Andreas Axén
Abstract Angiotensin IV analogs encompassing aromatic scaffolds replacing parts of the backbone of angiotensin IV have been synthesized and evaluated in biological assays. Several of the ligands displayed high affinities to the insulin-regulated aminopeptidase (IRAP)/AT4 receptor. Displacement of the C -terminal of angiotensin IV with an o -substituted aryl acetic acid derivative delivered the ligand 4, which exhibited the highest binding affinity (Ki = 1.9 nM). The high affinity of this ligand provides support to the hypothesis that angiotensin IV adopts a ,-turn in the C -terminal of its bioactive conformation. Ligand (4) inhibits both human IRAP and aminopeptidase N-activity and induces proliferation of adult neural stem cells at low concentrations. Furthermore, ligand 4 is degraded considerably more slowly in membrane preparations than angiotensin IV. Hence, it might constitute a suitable research tool for biological studies of the (IRAP)/AT4 receptor. Copyright © 2007 European Peptide Society and John Wiley & Sons, Ltd. [source]