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Free Content Editorial [ Hot Topic:Endocannabinoid-Binding Receptors: Old Friends and New Comers (Guest Editor: Mauro Maccarrone)]

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The plant Cannabis sativa produces ∼80 terpeno-phenol compounds, termed “phytocannabinoids”, among which Δ9- tetrahydrocannabinol (THC) is the most psychotropic component [1]. THC binds to specific G-protein-coupled receptors (GPCRs), named type-1 (CB1) and type-2 (CB2) cannabinoid receptors, that are also activated by endogenous ligands called “endocannabinoids” (eCBs). Among these lipid substances anandamide (N-arachidonoylethanolamine, AEA) was discovered as the first endogenous ligand of CB1 receptors, the most abundant GPCRs in mammalian brain. AEA is a prototype member of fatty acid amides, whereas 2-arachidonoylglycerol (2-AG) is the most prominent representative of monoacylglycerols, another group of eCBs [2]. Since the discovery of AEA and 2-AG, eCBs have received ever increasing attention, and their anti-cancer, anti-ischemic, anti-inflammatory, anti-depressant, anxiolytic, anorectic and bone-stimulant actions (just to list a few) are now widely recognized. This background has boosted pharmacological research, aimed at exploiting the therapeutic potential of eCBs-oriented drugs for the treatment of several diseases, both centrally and peripherally [3, 4].

AEA, 2-AG and other congeners interact with members of at least three of the four major classes of receptor proteins: GPCRs, ion channels (including ligand-gated ion channels), and nuclear receptors. In this context, it seems noteworthy that eCBs are able to interact with their receptors at binding sites exposed either extracellularly or intracellularly, and located within lipid rafts or in non-rafts microdomains [5]. Such a wealth of possibilities seems to underpin the critical role of eCBs-binding receptors in intra- and inter-cellular signalling [6, 7]. On this basis, eCBs-binding receptors are the focus of this Hot Topic issue of Current Medicinal Chemistry, where an update on CB1 [8] and CB2 [9] receptors will be presented, along with an overview of the other well-established target of AEA, the ion channel TRPV1 (transient receptor potential vanilloid-1) [10]. Furthermore, the actions of eCBs that engage nuclear receptors like peroxisome proliferator-activated receptors [11], and the pros and cons of the “orphan” G-protein-coupled receptor GPR55 as a true “type-3” (CB3) cannabinoid receptor will be discussed [12]. Overall, a complete survey of the eCBs-binding receptors best characterized to date will be presented. In addition, it should be stressed that even more candidates are emerging as targets of eCBs, like the transient receptor potential of melastatin-type 8 (TRPM8), that is antagonized by AEA [13], or the GPR119, which can recognize N-oleoylethanolamine and Npalmitoylethanolamine that are not ligands at classical CB receptors [14]. It seems evident that such a variety of potential triggers of endocannabinoid signalling has been disclosed by means of selective synthetic agonists or antagonists [15], and implies per se a variety of natural ligands in different cell types [16]. Furthermore, the determinants of ligand recognition by different receptors will be addressed in this Hot Topic issue [17], as will be the role of the membrane environment in ligand-receptor interaction [18].

Overall, I hope that this book can represent a useful instrument for the broad readership of Current Medicinal Chemistry, in order to get acquainted with one of the most exciting classes of molecules discovered at the end of the last millennium: the endocannabinoids. I expect that reading the chapters written by leading experts might foster novel ideas and boost new collaborations within the scientific community.

I wish to dedicate this book to Claudia, Giuseppe and Gianna.

Document Type: Research Article


Affiliations: Department of Biomedical Sciences University of Teramo Piazza Aldo Moro 45 64100 Teramo, Italy & Santa Lucia Foundation, Rome, Italy.

Publication date: May 1, 2010

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.

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