Chemical synthesis, pharmacological characterization, and possible formation in unicellular fungi of 3-hydroxy-anandamide

Abstract

The fungal pathogen Candida albicans transforms arachidonic acid (AA) into 3-hydroxyarachidonic acid [3(R)-HETE], and we investigated if its nonpathogenic and 3(R)-HETE-producing close relative, Dipodascopsis uninucleata, could similarly transform the endocannabinoid/endovanilloid anandamide into 3-hydroxyanandamide (3-HAEA). We found that D. uninucleata converts anandamide into 3-HAEA, and we therefore developed an enantiodivergent synthesis for this compound to study its pharmacological activity. Both enantiomers of 3-HAEA were as active as anandamide at ele- Supplementary key words cannabinoidFungi belonging to the Candida species (Ascomycetes; class Saccharomycetes) are among the most abundant fungal pathogens and cause of infections (candidiasis) in humans. They colonize a wide range of micro environments in the human body, and not only cause damage of the skin, nails, oral, or vaginal epithelium, but are also frequently involved in life-threatening infections. Candida species are opportunistic pathogens and cause nosocomial infections (disseminated candidiasis) that are particularly severe in cancer patients under chemotherapy or in immunocompromised individuals (1-6). They also cause mucocutaneous infections, such as vulvovaginal candidiasis, the most prevalent superficial fungal infection in women with acquired immunodeficiency syndrome (AIDS) and diabetes mellitus, or assuming oral contraceptives, antibiotics, and corticosteroids. The symptoms of vaginal candidiasis include itching, burning, soreness, abnormal vaginal discharge, dysparunia, as well as vaginal and vulvar erythema (7). C. albicans is the most prevalent pathogenic fungal species, and accounts for approximately 75% of all infections in women during the child-bearing period (8). Although C. albicans exists in the vagina of most of the women as an innocuous commensal organism with no apparent symptoms or clinical signs (9), it can also cause untreatable problems. Thus, due to its incomplete clearance by therapy with antimycotics, several women diagnosed with an episode of sporadic vulvovaginal infection experience subsequent recurrent episodes of acute vulvovaginitis.When looking at the major symptoms of candidiasis, particularly vulvar itching, burning, soreness, and erythema, it is possible to hypothesize that at least some of them

A re‐evaluation of 9‐HODE activity at TRPV1 channels in comparison with anandamide: enantioselectivity and effects at other TRP channels and in sensory neurons

“…In conclusion, from the present data, it seems unlikely that 9( S )‐HODE or (+/–)13‐HODE, rather than arachidonic acid derivatives, such as anandamide or 15( S )‐HAEA, are mostly responsible for tonic TRPV1 activity in the spinal cord during inflammatory pain, even accounting for their potentially higher concentrations or the presence of TRPV1‐sensitizing factors. Indeed, other oxidation products of arachidonic acid, such as the fungal metabolite 3‐HETE (De Petrocellis et al ., ), and the P450 arachidonic acid metabolite, 20‐HETE (Wen et al ., ), activate native and heterologously expressed TRPV1 with EC 50 values in the low micromolar range; whereas low nanomolar concentrations of derivatives from the oxidation of docosahexaenoic acid seem instead to act as indirect endogenous inhibitors of TRPV1 and TRPA1 (Park et al ., ). However, when these oxidative metabolites are generated in the periphery in inflammation, they might have different effects at primary afferent nerve terminals, when compared with those observed here on DRG cell bodies or transfected cells.…”

Non-CB1, Non-CB2 Receptors for Endocannabinoids, Plant Cannabinoids, and Synthetic Cannabimimetics: Focus on G-protein-coupled Receptors and Transient Receptor Potential Channels

“…By contrast, cyclization of the chain, as in prostaglandin ethanolamides (prostamides), abolishes activity at both receptor types (Matias et al 2004). By introducing a conformational constraint in the ethanolamine "head" of AEA and N-oleoylethanolamine, we recently demonstrated that the N-alkyl group of these ethanolamides has a different role in their interaction with cannabinoid or TRPV1 receptors (Appendino et al 2009). Interestingly, as reviewed recently (Oz et al 2006), the conformational flexibility of the acyl and N-alkyl chains of acylethanolamide endocannabinoids/endovanilloids allows them to interact also with several other molecular targets.…”

Skin Immunity to Candida albicans

“…C. albicans can also metabolize host arachnoid acid to bi-products that can directly activate nociceptor transient receptor potential cation channel subfamily V member 1(TRPV1) suggesting that multiple pathways of activation may exist. [59]. …”