Didier M Lambert

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CONTENTS

Introduction 109

Cannabis, Cannabinoids, and Endocannabinoid Signaling 109

3-Alkyl-(5,5'-Diphenyl)Imidazolidinediones as New Cannabinoid Receptor

Antagonists 111

Fatty Acid Amides Derived from N-Palmitoylethanolamine Interacting with

Anandamide Metabolism 117

Acknowledgments 120

References 120

INTRODUCTION

The aim of this chapter is to briefly review the molecular pharmacology of cannabinoids and to present thereafter our main research interests: (1) the synthesis and the pharmacological characterization of new cannabinoid-receptor antagonists and (2) the synthesis and biological evaluation of N-palmiloylethanolamine derivatives as new endocannabinoids interfering with the metabolism of anandamide.

CANNABIS, CANNABINOIDS, AND ENDOCANNABINOID SIGNALING

Among the plants known by humans since ancient times, the hemp Cannabis sativa has been widely used both for therapeutic, ritual, and recreational purposes. According to Chinese legend, the emperor Sheng Nung discovered the medicinal properties of three plants: ephedra, ginseng, and cannabis. The Chinese pharmacopoeia already described, in 200 B.C., the beneficial effects of cannabis for human health as well as the psychotropic properties of abuse. However, the isolation of the psychoactive ingredient of the plant, A9-tetrahydrocannabinol abbreviated here as THC, and its correct structure assignation were successfully achieved only in the mid-1960s by Professor Mechoulam at the Hebrew University.1 At that time, typical C21 terpenes isolated from the plant were named cannabinoids.

Nowadays, the term "cannabinoid" has been extended, at least by pharmacologists, to include all the compounds that bind to the cannabinoid receptors or other cannabinoid proteins. However, the isolation of THC did not solve the question of how THC and cannabis preparations act. Indeed, the sites of action, i.e., cannabinoid G-protein-coupled receptors (GPCR), were identified only in the late-1980s,2 first by biochemical evidence and finally by the cloning and sequencing of their respective cDNAs.3-5 One of the reasons for such a delay was the hydrophobic nature of THC, which does not facilitate its use as a radioligand.

Today, two different receptors are known, the cannabinoid CBj receptor found in the brain, the uterus, the lungs, and the testis, and the cannabinoid CB2 receptor, which is restricted to the membranes of cells from the immune system. The CB1 cannabinoid receptor was first evidenced by autoradiography and radioligand binding studies using [3H]-CP55940, a THC analogue less hydrophobic than its parent compound, and was cloned from rat, humans, and mouse. It is expressed in the brain and some peripheral tissues including testis, small intestine, urinary bladder, and vas deferens. An alternative spliced form of CBj, christened CB1A, has also been described, but thus far no peculiar property in terms of ligand recognition and receptor activation has been shown for this variant.6 The CB2 was discovered by sequence homology and is predominantly found in the immune system5 (spleen, tonsils, and

CBj Cannabinoid receptor

CB2 Cannabinoid receptor

Amino acid sequence

472 (human)

360 (human)

473 (mouse)

347 (mouse)

473 (rat)

360 (rat)

Localization

Brain, testis, uterus, lungs

Immune system

Receptor type

G protein coupled receptor

G protein coupled receptor

Main transduction mechanism

Adenylate cyclase, AMPc

Adenylate cyclase, AMPc

Homologies

Human-rat: 98% total,

Human-rat: 81% total

100% TM

Human-mouse: 83%

Human mouse: 97% total

Therapeutical interests

Pain

Pain

Appetite

Inflammation

Asthma

Immunity

Emesis

FIGURE 8.1 Comparison of the properties of the two subtypes of cannabinoid receptors (abbreviations: aa = amino acids; GPCR = G-protein-coupled receptor; TM = transmembrane

FIGURE 8.1 Comparison of the properties of the two subtypes of cannabinoid receptors (abbreviations: aa = amino acids; GPCR = G-protein-coupled receptor; TM = transmembrane immune cells). A comparative table illustrates the main characteristics of both receptors (Figure 8.1).

The discovery of cannabinoid receptors led to the identification of endogenous lipid compounds such as anandamide and 2-arachidonylglycerol, which bind to cannabinoid receptors. In 1993, Raphael Mechoulam, almost 30 years after his discovery of THC, proposed, together with William Devane, that an endogenous lipid, arachidonoylethanolamide, is the endogenous ligand of cannabinoid receptors.7 They christened the compound anandamide, as ananda in Sanskrit means internal bliss. Congeners have been identified, differing by the degree of unsaturation or the length of the arachidonoyl moiety. Some years later, almost at the same time, Mechoulam's team again, and the group of Sugiura in Japan, identified another endogenous lipid— not an amide, but an ester: the 2-arachidonoylgycerol. This compound has been proposed as the preferred endogenous CB2 agonist.

From a structural point of view, until now, agonists for these receptors belong to several distinct chemical classes:8 molecules derived from THC (usually named classical cannabinoid, and the close derivatives have been named nonclassical cannabi-noids), the aminoalkylindoles derived from pravadoline, and the fatty acid amides and esters derived from anandamide, the first described endogenous ligand (Figure 8.2). The diversity of structures is paralleled with the variety of origins: THC was isolated from a plant, pravadoline is a synthetic molecule, and anandamide was isolated from mammalian brain. Three classes of antagonists have been described thus far: SR 14I716A9 (Figure 8.2) and SR 14452810 (Figure 8.2) are diarylpyrazoles, LY-320135 is an arylbenzofuran,11 and AM630 is an aminoalkylindole.12 Point mutation studies as well as chimera CB1 and CB2 receptors provide new information on how these different ligands bind to the receptors. If agonists and antagonists have distinct sites inside the receptor (which is the case with most GPCR receptors), the point mutation studies indicated that some residues are crucial for some families of agonists but not for others (see the review by Reggio.13).

With the discovery of anandamide (arachidonoylelhanolamide) and, later, 2-ara-chidonylglycerol, a new signaling system has been identified.1415 Proteins have now been described either to trigger an intracellular signaling or to degrade the endocan-nabinoids. The first group of proteins involve cannabinoid receptors (CB1 and CB^, which are metabotropic receptors, and probably the vanilloid VR1 receptor, a calcium ligand-gated channel. The proteins involved in the degradation of anandamide neurotransmission include an active uptake protein that removes the endocannabinoids, and a degrading enzyme—the fatty acid amide hydrolase (FAAH) (Figure 8.3).

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