Functionalized Congeners of A3 Adenosine Receptor-Selective Nucleosides Containing a bicyclo[3.1.0]hexane Ring System

J Med Chem. 2009 Dec 10;52(23):7580-92. doi: 10.1021/jm900426g.

Abstract

(N)-Methanocarba nucleosides containing bicyclo[3.1.0]hexane replacement of the ribose ring previously demonstrated selectivity as A(3) adenosine receptor (AR) agonists (5'-uronamides) or antagonists (5'-truncated). Here, these two series were modified in parallel at the adenine C2 position. N(6)-3-Chlorobenzyl-5'-N-methyluronamides derivatives with functionalized 2-alkynyl chains of varying length terminating in a reactive carboxylate, ester, or amine group were full, potent human A(3)AR agonists. Flexibility of chain substitution allowed the conjugation with a fluorescent cyanine dye (Cy5) and biotin, resulting in binding K(i) values of 17 and 36 nM, respectively. The distal end of the chain was predicted by homology modeling to bind at the A(3)AR extracellular regions. Corresponding l-nucleosides were nearly inactive in AR binding. In the 5'-truncated nucleoside series, 2-Cl analogues were more potent at A(3)AR than 2-H and 2-F, functional efficacy in adenylate cyclase inhibition varied, and introduction of a 2-alkynyl chain greatly reduced affinity. SAR parallels between the two series lost stringency at distal positions. The most potent and selective novel compounds were amine congener 15 (K(i) = 2.1 nM) and truncated partial agonist 22 (K(i) = 4.9 nM).

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine A3 Receptor Agonists*
  • Adenosine A3 Receptor Antagonists*
  • Amides / chemistry
  • Animals
  • Bridged Bicyclo Compounds / chemistry*
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Conformation
  • Nucleosides / chemical synthesis
  • Nucleosides / chemistry*
  • Nucleosides / metabolism
  • Nucleosides / pharmacology*
  • Receptor, Adenosine A3 / chemistry
  • Receptor, Adenosine A3 / metabolism
  • Stereoisomerism
  • Substrate Specificity

Substances

  • Adenosine A3 Receptor Agonists
  • Adenosine A3 Receptor Antagonists
  • Amides
  • Bridged Bicyclo Compounds
  • Ligands
  • Nucleosides
  • Receptor, Adenosine A3
  • bicyclo(3.1.0)hexane