期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 21, 期 9, 页码 2740-2745出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2010.11.082
关键词
SCH 442416; G protein-coupled receptor; Fluorescence; Dendrimer; Radioligand binding
资金
- NIH
- National Institute of Diabetes and Digestive and Kidney Diseases
Pyrazolo[4,3-e][1,2,4] triazolo[1,5-c]pyrimidin-5-amine derivatives such as SCH 442416 display high affinity and selectivity as antagonists for the human A(2A) adenosine receptor (AR). We extended ether-linked chain substituents at the p-position of the phenyl group using optimized O-alkylation. The conjugates included an ester, carboxylic acid and amines (for amide condensation), an alkyne (for click chemistry), a fluoropropyl group (for F-18 incorporation), and fluorophore reporter groups (e. g., BODIPY conjugate 14, K-i 15 nM). The potent and A(2A)AR-selective N-aminoethylacetamide 7 and N-[2-(2-aminoethyl)-aminoethyl]acetamide 8 congeners were coupled to polyamidoamine (PAMAM) G3.5 dendrimers, and the multivalent conjugates displayed high A(2A)AR affinity. Theoretical docking of an AlexaFluor conjugate to the receptor X-ray structure highlighted the key interactions between the heterocyclic core and the binding pocket of the A(2A)AR as well as the distal anchoring of the fluorophore. In conclusion, we have synthesized a family of high affinity functionalized congeners as pharmacological probes for studying the A(2A)AR. Published by Elsevier Ltd.
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