Prostaglandin Ethanolamides (Prostamides): In Vitro Pharmacology and Metabolism

I. Matias, J. Chen, L. De Petrocellis, T. Bisogno, A. Ligresti, F. Fezza, A.H.-P. Krauss, L. Shi, C. E. Protzman, C. Li, Y. Liang, A. L. Nieves, K. M. Kedzie, R. M. Burk, V. Di Marzo, D. F. Woodward
J Pharmacol Exp Ther. 2004-02-02; 309(2): 745-757
DOI: 10.1124/jpet.103.061705

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1. J Pharmacol Exp Ther. 2004 May;309(2):745-57. doi: 10.1124/jpet.103.061705.
Epub 2004 Feb 2.

Prostaglandin ethanolamides (prostamides): in vitro pharmacology and metabolism.

Matias I(1), Chen J, De Petrocellis L, Bisogno T, Ligresti A, Fezza F, Krauss
AH, Shi L, Protzman CE, Li C, Liang Y, Nieves AL, Kedzie KM, Burk RM, Di Marzo
V, Woodward DF.

Author information:
(1)Endocannabinoid Research Group, Institute of Biomolecular Chemistry,
Consiglio Nazionale delle Ricerche, Napoli, Italy.

We investigated whether prostaglandin ethanolamides (prostamides) E(2),
F(2alpha), 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(2alpha) 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(2alpha) 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.

DOI: 10.1124/jpet.103.061705
PMID: 14757851 [Indexed for MEDLINE]

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