Dopamides, vanillylamides, ethanolamides, and arachidonic acid amides of anti-inflammatory and analgesic drug substances as TRPV1 ligands.
Drug substances can be acylated metabolically to give derivatives with specific and strong molecular effects. We generated potentially naturally occurring acid amides of several anti-inflammatory and analgesic drugs. In the amides, the drug moieties served either as amine or acid components. All compounds were evaluated for activity toward transient receptor potential vanilloid subfamily member 1 (TRPV1) in a cell-based Ca2+ influx assay; TRPV1 is a key receptor in the pain pathway and a promising target for analgesic drugs. We found that dopamine amides of fenamic acids have TRPV1 agonist activity in the nanomolar range, and that the arachidonoyl amide of a dipyrone metabolite has TRPV1 antagonist activity. Flufenamic acid dopamide, the most potent TRPV1 agonist reported herein, retains the cyclooxygenase (COX) inhibition properties of the parent compound flufenamic acid. Thus it acts on two different major players in the pain processing machinery. The compounds could be further keys to understanding the mechanism of action of fenamates and dipyrone at the molecular level. The fenamic acid dopamine amides qualify as new lead structures for drug development.
Sinning
Christian
C
Institut für Pharmazie, Martin-Luther-Universität, Wolfgang-Langenbeck-Str. 4, 06120 Halle, Germany.
Watzer
Bernhard
B
De Petrocellis
Luciano
L
Di Marzo
Vincenzo
V
Imming
Peter
P
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001095:Arachidonic Acids / Q000737:chemistry; D002478:Cells, Cultured; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004298:Dopamine / Q000737:chemistry; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D050916:TRPV Cation Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000577:Amides; D000700:Analgesics; D000893:Anti-Inflammatory Agents; D001095:Arachidonic Acids; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D004298:Dopamine