Prostaglandin Ethanolamides (Prostamides): In Vitro Pharmacology and Metabolism

Abstract

We investigated whether prostaglandin ethanolamides (prostamides) E 2 , F 2␣ , and D 2 exert some of their effects by 1) activating prostanoid receptors either per se or after conversion into the corresponding prostaglandins; 2) interacting with proteins for the inactivation of the endocannabinoid N-arachidonoylethanolamide (AEA), for example fatty acid amide hydrolase (FAAH), thereby enhancing AEA endogenous levels; or 3) activating the vanilloid receptor type-1 (TRPV1). Prostamides potently stimulated cat iris contraction with potency approaching that of the corresponding prostaglandins. However, prostamides D 2 , E 2 , and F 2␣ exhibited no meaningful interaction with the cat recombinant FP receptor, nor with human recombinant DP, EP 1-4 , FP, IP, and TP prostanoid receptors. Prostamide F 2␣ was also very weak or inactive in a panel of bioassays specific for the various prostanoid receptors. None of the prostamides inhibited AEA enzymatic hydrolysis by FAAH in cell homogenates, or AEA cellular uptake in intact cells. Furthermore, less than 3% of the compounds were hydrolyzed to the corresponding prostaglandins when incubated for 4 h with homogenates of rat brain, lung, or liver, and cat iris or ciliary body. Very little temperature-dependent uptake of prostamides was observed after incubation with rat brain synaptosomes or RBL-2H3 cells. We suggest that prostamides' most prominent pharmacological actions are not due to transformation into prostaglandins, activation of prostanoid receptors, enhancement of AEA levels, or gating of TRPV1 receptors, but possibly to interaction with novel receptors that seem to be functional in the cat iris.

Upregulation of orphan nuclear receptor Nur77 following PGF2α, Bimatoprost, and Butaprost treatments. Essential role of a protein kinase C pathway involved in EP2 receptor activated Nur77 gene transcription

“…Although their physiological actions have not been fully investigated, a synthetic prostamide analog (Bimatoprost) has been shown to be very potent in reducing IOP by increasing both uveosceral and trabecular outflow of aqueous humor (Woodward et al, 2001). The activities of prostamides as endogenous ligands at prostaglandin receptor(s) have been investigated, but have been shown to exert no meaningful activity (Berglund et al, 1999;Woodward et al, 2001;Ross et al, 2002;Matias et al, 2004). Studies on their metabolic rate clearly demonstrate that prostamides and their synthetic analog Bimatoprost exert their in vitro pharmacological effects (Matias et al, 2004) and the ocular hypotensive effects as the intact molecule .…”

“…The activities of prostamides as endogenous ligands at prostaglandin receptor(s) have been investigated, but have been shown to exert no meaningful activity (Berglund et al, 1999;Woodward et al, 2001;Ross et al, 2002;Matias et al, 2004). Studies on their metabolic rate clearly demonstrate that prostamides and their synthetic analog Bimatoprost exert their in vitro pharmacological effects (Matias et al, 2004) and the ocular hypotensive effects as the intact molecule . Experimental evidence suggests that prostamides may act as endogenous ligands at their own receptors (Woodward et al, 2001;Ross et al, 2002).…”

Enzymatic formation of prostamide F2α from anandamide involves a newly identified intermediate metabolite, prostamide H2

“…Although the physiological functions of the prostamides are not well defined, prostaglandin F 2 ␣ 1-ethanolamide (prostamide F 2 ␣ ) was reported to be potent in the contraction of the cat iris sphincter (9) and to behave as an effective ocular hypotensive agent in monkeys (10). In addition, the antiglaucoma drug bimatoprost (Lumigan™) is similar to prostamide F 2 ␣ in structure and behaves as a prostamide analog (9,10).…”

Interaction of Ocular Hypotensive Agents (PGF2α Analogs—Bimatoprost, Latanoprost, and Travoprost) With MDR Efflux Pumps on the Rabbit Cornea

“…Various reports indicate that bimatoprost, which is an ethyl amide prodrug of 17-phenyl-PGF2α, is classifi ed as a prostamide and exerts its action in lowering intraocular pressure (IOP) through a novel prostamide receptor. [18][19][20][21] On the other hand, its metabolite, bimatoprost-free acid ) is also shown to lower the IOP by interacting with prostanoid FP receptors, thus being classifi ed as a potent FP receptor agonist. [22][23][24] On the contrary, both latanoprost and and MRP5 on the human as well as rabbit primary corneal epithelial cells.…”