Pyrazolo[1',5':1,6]pyrimido[4,5-d]pyridazin-4(3H)-ones as selective human A(1) adenosine receptor ligands

Bioorg Med Chem. 2010 Nov 15;18(22):7890-9. doi: 10.1016/j.bmc.2010.09.043. Epub 2010 Sep 22.

Abstract

A series of pyrazolo[1',5':1,6]pyrimido[4,5-d]pyridazin-4(3H)-ones was synthesized and tested in radioligand binding assays to determine their affinities for the human adenosine A(1), A(2A), A(2B) and A(3) receptors. Results indicated that this scaffold is appropriate for adenosine receptor subtype A(1) ligands and that the best arranged groups around this scaffold are 3- and 4-pyridinyl at position 1, benzyl at position 3, hydrogen at position 6 and 3-thienyl or phenyl at position 9. The most interesting compounds showed K(i) for A1 in the nanomolar range and an appreciable selectivity for other receptor subtypes.

MeSH terms

  • Adenosine A1 Receptor Antagonists / chemical synthesis
  • Adenosine A1 Receptor Antagonists / chemistry*
  • Adenosine A1 Receptor Antagonists / pharmacology
  • Cell Line
  • Humans
  • Ligands
  • Protein Binding
  • Pyrazoles / chemistry*
  • Pyridazines / chemical synthesis
  • Pyridazines / chemistry*
  • Pyridazines / pharmacology
  • Pyrimidines / chemistry*
  • Receptor, Adenosine A1 / chemistry*
  • Receptor, Adenosine A1 / metabolism
  • Receptor, Adenosine A2A / chemistry
  • Receptor, Adenosine A2A / metabolism
  • Receptor, Adenosine A2B / chemistry
  • Receptor, Adenosine A2B / metabolism
  • Receptor, Adenosine A3 / chemistry
  • Receptor, Adenosine A3 / metabolism

Substances

  • Adenosine A1 Receptor Antagonists
  • Ligands
  • Pyrazoles
  • Pyridazines
  • Pyrimidines
  • Receptor, Adenosine A1
  • Receptor, Adenosine A2A
  • Receptor, Adenosine A2B
  • Receptor, Adenosine A3
  • pyrimidine