Synthesis and evaluation of phorboid 20-homovanillates: discovery of a class of ligands binding to the vanilloid (capsaicin) receptor with different degrees of cooperativity

J Med Chem. 1996 Aug 2;39(16):3123-31. doi: 10.1021/jm960063l.


A number of phorboid 20-homovanillates were prepared by condensation of phorbol 12,13-diesters and 12-dehydrophorbol 13-esters with Mem-homovanillic acid followed by removal of the protecting group with SnCl4 in THF. These compounds were evaluated for their ability to inhibit [3H]resiniferatoxin (RTX) binding to rat spinal cord membranes. Compounds bearing a lipophilic ester group on ring C were considerably active, but a surprising tolerance of the vanilloid receptor toward the location and the orientation of this ester group was disclosed. Unexpectedly, these ligands could also diminish, to a variable degree, the positive cooperativity which characterizes RTX binding to the vanilloid receptor. Phorbol 12-phenylacetate 13-acetate 20-homovanillate (PPAHV, 6a), a compound which abolished binding cooperativity, was further tested in a variety of in vivo assay used to characterize vanilloid-like activity. PPAHV showed only a marginal pungency and failed to induce a measurable hypothermia response at doses (up to 200 mg/kg) at which it effectively desensitized against neurogenic inflammation. These data suggest that the peculiar binding behavior of these ligands might be associated with a distinct spectrum of biological activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Temperature / drug effects
  • Diterpenes / metabolism
  • Diterpenes / pharmacology
  • Edema / chemically induced
  • Homovanillic Acid / analogs & derivatives*
  • Homovanillic Acid / metabolism
  • Homovanillic Acid / pharmacology*
  • Magnetic Resonance Spectroscopy
  • Mass Spectrometry
  • Membrane Proteins / metabolism
  • Molecular Structure
  • Phorbol Esters / chemical synthesis*
  • Phorbol Esters / metabolism
  • Phorbol Esters / pharmacology*
  • Protein Binding
  • Rats
  • Receptors, Drug / agonists*
  • Receptors, Drug / metabolism
  • Spinal Cord / drug effects
  • Spinal Cord / metabolism


  • Diterpenes
  • Membrane Proteins
  • Phorbol Esters
  • Receptors, Drug
  • phorbol 12-phenylacetate 13-acetate 20-homovanillate
  • resiniferatoxin
  • Homovanillic Acid