title: Prostaglandin ethanolamides (prostamides): in vitro pharmacology and metabolism.
abstract: 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.
authors.affiliation: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Napoli, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Matias
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.forename: L
authors.initials: L
authors.lastname: De Petrocellis
authors.forename: T
authors.initials: T
authors.lastname: Bisogno
authors.forename: A
authors.initials: A
authors.lastname: Ligresti
authors.forename: F
authors.initials: F
authors.lastname: Fezza
authors.forename: A H-P
authors.initials: AH
authors.lastname: Krauss
authors.forename: L
authors.initials: L
authors.lastname: Shi
authors.forename: C E
authors.initials: CE
authors.lastname: Protzman
authors.forename: C
authors.initials: C
authors.lastname: Li
authors.forename: Y
authors.initials: Y
authors.lastname: Liang
authors.forename: A L
authors.initials: AL
authors.lastname: Nieves
authors.forename: K M
authors.initials: KM
authors.lastname: Kedzie
authors.forename: R M
authors.initials: RM
authors.lastname: Burk
authors.forename: V
authors.initials: V
authors.lastname: Di Marzo
authors.forename: D F
authors.initials: DF
authors.lastname: Woodward
mesh_terms: D000577:Amides / Q000378:metabolism / Q000494:pharmacology*; D000581:Amidohydrolases / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D002415:Cats; D002460:Cell Line; D063388:Endocannabinoids; D004983:Ethanolamines / Q000378:metabolism / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D006868:Hydrolysis; D007498:Iris / Q000187:drug effects / Q000502:physiology; D007601:Jugular Veins / Q000187:drug effects / Q000502:physiology; D051379:Mice; D053284:Polyunsaturated Alkamides; D011453:Prostaglandins / Q000378:metabolism / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D011955:Receptors, Drug / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013574:Synaptosomes / Q000378:metabolism; D050916:TRPV Cation Channels; D014407:Tumor Cells, Cultured; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000577:Amides; D000581:Amidohydrolases; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D004983:Ethanolamines; D053284:Polyunsaturated Alkamides; D011453:Prostaglandins; D011955:Receptors, Drug; D011982:Receptors, Prostaglandin; D011994:Recombinant Proteins; D050916:TRPV Cation Channels; D000099252:Fatty Acid Amide Hydrolases; C494484:TRPV1 receptor; C034671:prostaglandin F2alpha receptor; C078814:anandamide