title: Molecular probes for the A2A adenosine receptor based on a pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine scaffold.
abstract: 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 (18)F 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.
authors.affiliation: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bldg. 8A, Rm. B1A-19, Bethesda, MD 20892, USA.
authors.forename: T Santhosh
authors.initials: TS
authors.lastname: Kumar
authors.forename: Shilpi
authors.initials: S
authors.lastname: Mishra
authors.forename: Francesca
authors.initials: F
authors.lastname: Deflorian
authors.forename: Lena S
authors.initials: LS
authors.lastname: Yoo
authors.forename: Khai
authors.initials: K
authors.lastname: Phan
authors.forename: Miklos
authors.initials: M
authors.lastname: Kecskés
authors.forename: Angela
authors.initials: A
authors.lastname: Szabo
authors.forename: Bidhan
authors.initials: B
authors.lastname: Shinkre
authors.forename: Zhan-Guo
authors.initials: ZG
authors.lastname: Gao
authors.forename: William
authors.initials: W
authors.lastname: Trenkle
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
mesh_terms: D058917:Adenosine A2 Receptor Antagonists; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D015335:Molecular Probes / Q000138:chemical synthesis / Q000737:chemistry; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D015335:Molecular Probes; D011720:Pyrazoles; D011743:Pyrimidines