Synthesis and evaluation of phorboid 20-homovanillates: discovery of a class of ligands binding to the vanilloid (capsaicin) receptor with different degrees of cooperativity.
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.
Appendino
G
G
Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
Cravotto
G
G
Palmisano
G
G
Annunziata
R
R
Szallasi
A
A
D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D004224:Diterpenes / Q000378:metabolism / Q000494:pharmacology; D004487:Edema / Q000139:chemically induced; D006719:Homovanillic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008565:Membrane Proteins / Q000378:metabolism; D015394:Molecular Structure; D010703:Phorbol Esters / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D011955:Receptors, Drug / Q000819:agonists* / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism
D004224:Diterpenes; D008565:Membrane Proteins; D010703:Phorbol Esters; D011955:Receptors, Drug; C100823:phorbol 12-phenylacetate 13-acetate 20-homovanillate; C024353:resiniferatoxin; D006719:Homovanillic Acid