Partial QSAR Analysis of Some Selected Natural Inhibitors of FAAH Suggests a Working Hypothesis for the Development of Endocannabinoid- Based Drugs

Authors: Dainese, Enrico; Gasperi, Valeria; Maccarrone, Mauro

Source: Current Drug Targets-CNS & Neurological Disorders, Volume 4, Number 6, December 2005 , pp. 709-714(6)

Publisher: Bentham Science Publishers

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Abstract:

The endogenous cannabinoids (endocannabinoids) are bioactive signaling molecules, that show diverse cellular and physiological effects and play various roles in the central nervous system, as well as in the periphery. The discovery of N-arachidonoylethanolamine (anandamide, AEA) and of the enzyme that terminates its signaling, i. e. fatty acid amide hydrolase (FAAH), has inspired pharmacological strategies to augment endocannabinoid tone and biological activity through inhibition of FAAH. Here we discuss the role of natural endocannabinoid derivatives, like the hydroxyanandamides (OH-AEAs) generated from AEA via lipoxygenase activity, as powerful inhibitors of FAAH. We propose that these compounds, by reversibly inhibiting FAAH, may control in vivo the endocannabinoid tone. We consider the theoretical structural properties of OH-AEAs and other natural inhibitors of FAAH, based on the calculation of theoretical molecular descriptors commonly used in Quantitative Structure Activity Relationship (QSAR) studies. The QSAR properties of OH-AEAs and congeners suggest that they could act at different specific sites of FAAH, thus confirming their potential value as templates for the development of next-generation therapeutics.

Keywords: anandamide hydrolase; endocannabinoids; inhibition; lipoxygenase; molecular modeling; nervous system; QSAR; therapy

Document Type: Review article

DOI: http://dx.doi.org/10.2174/156800705774933096

Affiliations: 1: Department of Biomedical Sciences, University of Teramo, Piazza A. Moro 45, 64100 Teramo, Italy.

Publication date: 2005-12-01

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CNS & Neurological Disorders - Drug Targets aims to cover all the latest and outstanding developments on the medicinal chemistry, pharmacology, molecular biology, genomics and biochemistry of contemporary molecular targets involved in neurological and central nervous system (CNS) disorders e.g. disease specific proteins, receptors, enzymes, genes. Each issue of the journal will contain a series of timely in-depth reviews written by leaders in the field covering a range of current topics on drug targets involved in neurological and CNS disorders. As the discovery, identification, characterization and validation of novel human drug targets for neurological and CNS drug discovery continues to grow; this journal will be essential reading for all pharmaceutical scientists involved in drug discovery and development.

Partial QSAR Analysis of Some Selected Natural Inhibitors of FAAH Suggests a Working Hypothesis for the Development of Endocannabinoid- Based Drugs

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