AEA Oxidation Products

The AEA oxidation products produced from the initial COX-2-derived products have been named prostamides (after prostaglandin-ethanolamides) (Figure 6.3) (Woodward et al., 2000). Prostamides are 2 to 3 orders of magnitude less active than the corresponding prostaglandins (PGs) in both binding and functional assays of the several prostanoid receptors known to date (Ross et al., 2002; Woodward et al., 2001; 2003). For example, prostamide E2 is 100 to 1000-fold less potent than PGE2 in binding assays carried out with EP1, EP2, EP3, and EP4 receptor-containing membranes. However, although this compound is, as expected, about 100-fold less potent than the free acid in functional assays of EP3 and EP4 receptors, it is also surprisingly only 15 times less potent than PGE2 in a functional assay of EP2 receptors, the relaxation of histamine-induced contractions of guinea pig trachea (Ross et al., 2002). Prostamide F2 and its 17-phenyl-derivative, bimatoprost (AGN192024, LumiganĀ®) (Figure 6.3) exhibit very low affinity for, and potency at, the FP receptor, although they both exert a powerful contraction of the isolated feline iris sphincter and potently reduce the intraocular pressure in ocular normotensive dogs (Woodward et al., 2000; 2001). Bimatoprost and prostamide F2 were suggested to act on yet uncharacterized novel receptors because they exert also a strong contraction of feline lung parenchyma at low nanomolar concentrations, although they have an altogether different pharmacological profile from PGF2 in all the other available assays for FP-receptor-mediated activity, and exert no activity in a wide range of binding assays for other known receptors (Woodward et al., 2001; 2003).

Regarding AEA metabolites obtained from lipoxygenases, their potential capability of stimulating VR1 receptors, hypothesized so far only on the basis of pharmacological evidence, has been mentioned in the preceding text. Interestingly, a preliminary report has suggested that the leukotriene B4 derivative of AEA (Figure 6.3) might also activate VR1 with the same potency as LTB4 (McHugh et al., 2003).

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