Biochanin A, a naturally occurring inhibitor of fatty acid amide hydrolase

Abstract

Background and purpose: Inhibitors of fatty acid amide hydrolase (FAAH), the enzyme responsible for the metabolism of the endogenous cannabinoid (CB) receptor ligand anandamide (AEA), are effective in a number of animal models of pain. Here, we investigated a series of isoflavones with respect to their abilities to inhibit FAAH. Experimental approach: In vitro assays of FAAH activity and affinity for CB receptors were used to characterize key compounds. In vivo assays used were biochemical responses to formalin in anaesthetized mice and the 'tetrad' test for central CB receptor activation. Key results: Of the compounds tested, biochanin A was adjudged to be the most promising. Biochanin A inhibited the hydrolysis of 0.5 mM AEA by mouse, rat and human FAAH with IC50 values of 1.8, 1.4 and 2.4 mM respectively. The compound did not interact to any major extent with CB1 or CB2 receptors, nor with FAAH-2. In anaesthetized mice, URB597 (30 mg i.pl.) and biochanin A (100 mg i.pl.) both inhibited the spinal phosphorylation of extracellular signal-regulated 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 mg i.pl.). Biochanin A (15 mg·kg -1 i.v.) did not increase brain AEA concentrations, but produced a modest potentiation of the effects of 10 mg·kg -1 i.v. AEA in the tetrad test. Conclusions and implications: It is concluded that biochanin A, in addition to its other biochemical properties, inhibits FAAH both in vitro and peripherally in vivo.

Biochanin-A attenuates neuropathic pain in diabetic rats

“…Previous in-vivo study reported that biochanin-A is a naturally occurring inhibitor of FAAH, which metabolites endocannabinoids [20]. However, the efficacy of biochanin-A is higher at 2 h post-dose in both hyperalgesia and allodynia.…”

“…Thus, biochanin-A behaved like URB597 after local administration to the paw [20]. Thus, biochanin-A could be suitable drug candidate for neuropathic pain patients in alleviating majorly mechanical allodynia and moderately mechanical hyperalgesia.…”

“…Biochanin-A was a mixed-type inhibitor of the rat FAAH and showed similar low micromolar potencies towards rat, mouse and recombinant human FAAH [20].…”

Parabens inhibit fatty acid amide hydrolase: A potential role in paraben-enhanced 3T3-L1 adipocyte differentiation

“…However, since the interaction is mixed-type instead of competitive, the relative K i will never be higher than 1 μM. Isoflavones, including Biochanin A, have been reported to inhibit FAAH in a similar mixed-type fashion (Thors et al, 2010). Several of these isoflavones have similar structural features including a para phenol to the carbonyl group.…”

N-(4-Methoxy-2-nitrophenyl)hexadecanamide, a palmitoylethanolamide analogue, reduces formalin-induced nociception

“…Given that both AEA (via CB 1 cannabinoid receptors) and 2-AG (via CB 2 cannabinoid receptors) are efficacious in the formalin test when given locally to the hind paws of rats (Guindon et al, 2006(Guindon et al, , 2007, and that FAAH inhibitors reduce the behavioral and biochemical consequences of formalin in this test (Lichtman et al, 2004;Sit et al, 2007;Clapper et al, 2010;Thors et al, 2010), inhibition of FAAH could in theory be involved in the action of HD. The compound, however, was a rather weak inhibitor of FAAH in vitro, producing inhibition of AEA hydrolysis only at concentrations of 20 μM and higher.…”