Biochanin A acts as a peripheral inhibitor of fatty acid amide hydrolase
(English)Manuscript (Other academic)
Inhibitors of fatty acid amide hydrolase (FAAH), the enzyme primarily responsible for the metabolism of the endogenous cannabinoid (CB) receptor ligand anandamide, are effective in animal models of inflammatory, cancer, visceral and neuropathic pain. No peripherallyrestricted FAAH inhibitors have yet been reported. The isoflavones are a class of naturallyoccurring compounds that show little brain penetration, and two of these, genistein and daidzein, inhibit FAAH at low micromolar concentrations. Here, we report that the related isoflavone biochanin A inhibits the hydrolysis of 0.5 μM anandamide by mouse, rat and human FAAH with IC50 values of 1.8, 1.4, and 2.4 μM, respectively. The inhibition of rat FAAH by biochanin A was mixed type in nature, with Ki slope and Ki intercept values of 1.1 and 8.2 μM, respectively. Anandamide hydrolysis was also inhibited in intact basophilic leukaemia cells at sub- to low- micromolar concentrations. The compound did not interact to any major extent with CB1 or CB2 receptors. In vivo, biochanin A (10 mg/kg i.v.) did not increase brain anandamide concentrations, but produced a modest potentiation of the effects of 10 mg/kg i.v. anandamide in the tetrad test. In anaesthetized mice, URB597 (30 μg/paw) and biochanin A (100 μg/paw) both inhibited the spinal phosphorylation of extracellular receptor kinase produced by the intraplantar injection of formalin. The effects of both compounds were significantly reduced by the CB1 receptor antagonist/inverse agonist AM251 (30 μg/paw). It is concluded that biochanin A may be useful as a template for the design of novel, peripherally-acting FAAH inhibitors.
fatty acid amide hydrolase; inflammatory pain; cannabinoid; isoflavones, biochanin A; anandamide
Pharmacology and Toxicology
IdentifiersURN: urn:nbn:se:umu:diva-22172OAI: oai:DiVA.org:umu-22172DiVA: diva2:213032