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Modifications of the ethanolamine head in N-palmitoylethanolamine: synthesis and evaluation of new agents interfering with the metabolism of anandamide.
Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience.
Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience.
2003 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, Vol. 46, no 8, 1440-1448 p.Article in journal (Refereed) Published
Abstract [en]

The endogenous fatty acid amide anandamide (AEA) has, as a result of its actions on cannabinoid and vanilloid receptors, a number of important pharmacological properties including effects on nociception, memory processes, spasticity, and cell proliferation. Inhibition of the metabolism of AEA, catalyzed by fatty acid amide hydrolase (FAAH), potentiates the actions of AEA in vivo and therefore may be a useful target for drug development. In the present study, we have investigated whether substitution of the headgroup of the endogenous alternative FAAH substrate palmitoylethanolamide (PEA) can result in the identification of novel compounds preventing AEA metabolism. Thirty-seven derivatives of PEA were synthesized, with the C16 long chain of palmitic acid kept intact, and comprising 20 alkylated, 12 aromatic, and 4 halogenated amides. The ability of the PEA derivatives to inhibit FAAH-catalyzed hydrolysis of [(3)H]AEA was investigated using rat brain homogenates as a source of FAAH. Inhibition curves were analyzed to determine the potency of the inhibitable fraction (pI(50) values) and the maximal attained inhibition for the compound, given that solubility in an aqueous environment is a major issue for these compounds. In the alkylamide family, palmitoylethylamide and palmitoylallylamide were inhibitors of AEA metabolism with pI(50) values of 5.45 and 5.47, respectively. Halogenated derivatives (Cl and Br) exhibit pI(50) values of approximately 5.5 but rather low percentages of maximal inhibition. The -OH group of the ethyl head chain of N-palmitoylethanolamine was not necessary for interaction with FAAH. Amides containing aromatic moieties were less potent inhibitors of AEA metabolism. Compounds containing amide and ester bonds, 13 and 37, showed pI(50) values of 4.99 and 5.08, respectively. None of the compounds showed obvious affinity for CB(1) or CB(2) receptors expressed on Chinese hamster ovary (CHO) cells. It is concluded that although none of the compounds were dramatically more potent than PEA itself at reducing the metabolism of AEA, the lack of effect of the compounds at CB(1) and CB(2) receptors makes them useful templates for development of possible therapeutic FAAH inhibitors.

Place, publisher, year, edition, pages
2003. Vol. 46, no 8, 1440-1448 p.
URN: urn:nbn:se:umu:diva-4393DOI: 10.1021/jm0209679PubMedID: 12672243OAI: diva2:143472
Available from: 2005-02-09 Created: 2005-02-09 Last updated: 2009-11-16Bibliographically approved
In thesis
1. Pharmacology of Palmitoylethanolamide and Related Compounds
Open this publication in new window or tab >>Pharmacology of Palmitoylethanolamide and Related Compounds
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Anandamide (AEA) is an endogenous fatty acid which activates the same cannabinoid receptors as ∆9-tetrahydrocannabinol, the psychoactive substance in marijuana. In vivo, anandamide exerts a number of actions including effects upon pain and inflammation. However, AEA has a short duration of action since it is rapidly metabolised, primarily by the intracellular enzyme fatty acid amide hydrolase (FAAH).

The general aim of this thesis has been to identify and characterize compounds capable of preventing the metabolism of anandamide. The chemical approach was based on the endogenous anti-inflammatory compound palmitoylethanolamide (PEA), a compound related to anandamide with the ability to inhibit anandamide degradation by substrate competition, but without the ability to directly activate cannabinoid receptors.

A number of compounds were identified as inhibitors of rat brain FAAH in the initial in vitro studies, without having major affinity for the cannabinoid receptors. In particular, palmitoylisopropylamide (PIA) was found to reduce the metabolism of AEA in intact C6 glioma cells with potency similar to the prototypical AEA reuptake inhibitor AM404. This compound was in addition found to exert less effect upon C6 glioma cell proliferation than either AM404 or the closely related uptake inhibitor VDM11. To evaluate if PIA was effective in vivo, a model of mast cell dependent inflammation, oedema of the ear following local injection of compound 48/80, was set up using anaesthetised mice. Initially, a CB2 cannabinoid receptor selective agonist was used to probe the model and demonstrated to produce an anti-oedema effect. In contrast, the compound was inactive in vitro in skin slice preparations. PIA showed a similar pattern, although there was a large variation in responses which affected the significance of the result obtained, as did the vehicle used to dissolve the compound.

Taken together, the present data would suggest that PIA can inhibit the degradation of AEA without having deleterious effects upon cell proliferation or affinity for the cannabinoid receptors. Further experimentation is necessary to elucidate the usefulness of this compound in vivo.

Place, publisher, year, edition, pages
Umeå: Farmakologi och klinisk neurovetenskap, 2005. 82 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 942
Pharmacology, anandamide, cannabinoid, FAAH, palmitoylethanolamide, palmitoylisopropylamide, inflammation, mast cells, Farmakologi
National Category
Pharmacology and Toxicology
Research subject
Medical Pharmacology
urn:nbn:se:umu:diva-445 (URN)91-7305-821-1 (ISBN)
Public defence
2005-03-04, E04, 6E, Norrlands universitetssjukhus, Umeå, 09:00 (English)
Available from: 2005-02-09 Created: 2005-02-09 Last updated: 2009-11-17Bibliographically approved

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