Synthesis of a tritium-labeled indolidan analogue and its use as a radioligand for phosphodiesterase-inhibitor cardiotonic binding sites

J Med Chem. 1989 Jul;32(7):1476-80. doi: 10.1021/jm00127a014.

Abstract

We have radiolabeled a structural analogue of indolidan, a potent phosphodiesterase-inhibitor cardiotonic, to permit biochemical studies regarding the interaction of this class of drugs with their pharmacological receptor. [3H]-LY186126 (1,3-dihydro-3,3-dimethyl-1-[3H3]methyl-5-(1,4,5,6-tetrahydro-4-me thyl-6- oxo-3-pyridazinyl)-2H-indol-2-one; [3H]-3) was selected as a synthetic target because of its potency as a cardiotonic and the ability to readily incorporate three tritia via the indolone N-CH3 substituent. Alkylation of a desmethyl precursor with tritium-labeled iodomethane resulted in [3H]-3 with a radiochemical purity of 98% and a specific activity of 79.2 Ci/mmol. This radioligand binds with high affinity to myocardial membrane vesicles. The binding was saturable, and Kd and Bmax values of 4.1 nM and 383 fmol/mg protein were obtained. A series of indolidan congeners displaced [3H]-3 bound to myocardial vesicles, and Ki values for inhibition of binding were highly correlated with canine inotropic ED50 values, suggesting the specific binding of [3H]-3 to cardiac vesicles is pharmacologically relevant.

MeSH terms

  • Animals
  • Binding Sites
  • Chemical Phenomena
  • Chemistry
  • Dogs
  • Female
  • Indoles / chemical synthesis*
  • Indoles / metabolism
  • Ligands
  • Male
  • Myocardium / metabolism*
  • Oxindoles
  • Phosphodiesterase Inhibitors / metabolism*
  • Pyridazines / chemical synthesis*
  • Pyridazines / metabolism
  • Radioligand Assay
  • Spectrophotometry, Ultraviolet
  • Tritium

Substances

  • Indoles
  • Ligands
  • Oxindoles
  • Phosphodiesterase Inhibitors
  • Pyridazines
  • indolidan
  • Tritium
  • LY 186126