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CELLULAR AND MOLECULAR

Prostaglandin Ethanolamides (Prostamides): In Vitro Pharmacology and Metabolism

Endocannabinoid Research Group, Institute of Biomolecular Chemistry (I.M., T.B., A.L., F.F., V.D.M.) and Institute of Cybernetics (L.D.P.), Consiglio Nazionale delle Ricerche, Napoli, Italy; and Departments of Chemical (R.M.B.) and Biological Sciences (J.C., A.H.-P.K., L.S., C.E.P., C.L., Y.L., A.L.N., K.M.K., D.F.W.), Allergan, Inc., Irvine, California

We investigated whether prostaglandin ethanolamides (prostamides) E₂, F₂, and D₂ 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 D₂, E₂, and F₂ 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 F₂ 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.

Address correspondence to: Dr. David F. Woodward, Department of Biological Sciences, Allergan, Inc., 2525 Dupont Dr. (RD-2C), Irvine, CA 92612. E-mail: woodward_david{at}allergan.com

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