Cannabinoids

Vincenzo Di Marzo

• Publisher: Wiley-Blackwell
• Year: 2014
• ISBN:
  9781118451274
• Edition: 1
• Topic: Biological Sciences
• Subtopic: Zoology
• Index: Biological Sciences

Cannabinoids

'Cannabinoids' is a broad term covering a group of natural products from Cannabis sativa, one of which locks on to specific receptors – protein molecules on the surface of cells – known as cannabinoid receptors. Over the past decades scientists have found that cannabinoid receptors and their endogenous ligands, the endocannabinoids, are involved in a vast array of physiological functions, including helping to control brain activity, energy metabolism, heart function, the immune system and even reproduction.

In Cannabinoids, Vincenzo Di Marzo has assembled contributions from international experts to provide the definitive guide to what continues to be a rapidly developing research field. After an introductory historical chapter, the book continues by looking at the biochemical, genetic and molecular elements of cannabinoids, followed by chapters covering their role in health and disease. The final chapter outlines the need for a new nomenclature to reflect the complex and multi-disciplinary nature of this area.

• An authoritative guide to the history, development and possible future of cannabinoid research.
• Includes contributions from leading international experts in the field.
• Clearly written, well organised and logically presented.

Cannabinoids will prove invaluable to researchers, practitioners and students across a wide range of disciplines, needing an up-to-date guide to this significant area of research.

Chapter 1
Looking ahead after 50 years of research on cannabinoids

Raphael Mechoulam

Institute for Drug Research, Hebrew University Medical Faculty, Jerusalem, Israel

1.1 Summary

My lab has been involved in research on cannabis and endogenous cannabinoids for 50 years. In this overview I first summarise some of our work over these decades. Then, on the basis of previous research, I speculate on a few of the pathways cannabinoid investigations may follow in the future. Two possible research trends are discussed:

1. Cannabidiol—effects and mechanisms.
2. Fatty acid amides of amino acids and related endogenous molecules—biological roles.

1.2 Introduction

Cannabis research has a long and convoluted history. The first chemical endeavours were published in the 1840s. Around the end of the nineteenth century, crystalline cannabinol acetate was obtained after acetylation of an extract of hashish. Its structure was elucidated in the 1930s, when cannabidiol (CBD) was also isolated, but only a partial structure for it was put forward. Roger Adams and Alexander Todd published numerous, mostly synthetic, papers on cannabis and found that some synthetic tricyclic compounds had cannabis-like activity in dogs. Loewe (1950) summarised the pharmacological work on cannabis extracts and synthetic compounds carried out over a century. For early reviews, with an emphasis on the chemical aspects, see Mechoulam and Gaoni (1967a) and Mechoulam (1973).

Clinical research with cannabis was also undertaken in the nineteenth century. In the 1840s, the psychiatrist J. J. Moreau conducted a clinical experiment in which he administered hashish to humans. His volunteers, including Moreau himself, experienced ‘occurrences of delirium or of actual madness …’. He concluded that ‘There is not a single, elementary manifestation of mental illness that cannot be found in the mental changes caused by hashish …’ (Moreau, 1973). Marijuana users today mostly report different effects. One can only wonder what amounts were administered by Moreau to his volunteers.

Modern pharmacological and clinical research is done with precise doses of active compounds. The absence of a well-established chemical basis of cannabis until the mid 1960s, made biological and clinical research with it of very limited value. Novel approaches to elucidate the chemistry of cannabis, in order to proceed with biological evaluations, were badly needed.

I started research on cannabis in 1963. Initially I assumed that the project would be completed within a few years. Today—50 years later—my group is still looking at various aspects of cannabis chemistry and pharmacology.

As methods for both separation and structural elucidation by physical techniques were, in the early 1960s, considerably more advanced than those employed by Adams and Todd in the 1930s and 1940s, we assumed that we could solve some of the problems previously encountered. I started with re-isolation of cannabidiol (CBD) by a series of column chromatographies and the elucidation of its structure by NMR, a technique which had just been introduced in organic chemistry (Mechoulam and Shvo, 1963). Then Yehiel Gaoni joined me on the project and we approached the problem of isolation of the active compound (or compounds). We needed biological feedback to identify the active material. Habib Edery and Yona Grunfeld in the nearby Institute for Biological Research had a group of rhesus monkeys which, luckily for us, were rapidly sedated on administration of some chromatographic fractions isolated from cannabis. We concentrated our work on these fractions, and in 1964 we reported that we had identified a single active compound, Δ⁹-tetrahydrocannabinol (THC) and had elucidated its structure (Gaoni and Mechoulam, 1964). Later we reported its total synthesis and absolute configuration (Mechoulam et al., 1967; Mechoulam and Gaoni, 1967b). Over the next few years we isolated numerous additional cannabinoids—a term we coined for this group of compounds. Cannabigerol, cannabichromene, cannabicyclol, cannabidiolic acid and cannabielsoic acid among them. None of them showed THC-like activity, and we finally stated that ‘… except for THC, no other major active compounds were present in the analyzed sample of hashish’ (Mechoulam et al., 1970, 1976). Over the years, dozens of new cannabinoids, mostly minor constituents, have been identified in various cannabis strains (Figure 1.1). None has shown marijuana-like activity.

Figure 1.1 Cannabinoids within Cannabis sativa

The next step followed in our laboratory was investigation of the metabolism of cannabinoids. Together with colleagues in the USA, UK, Sweden and later Japan we elucidated several metabolic pathways. By now several groups had become involved in cannabinoid investigations and four groups simultaneously reported the first steps of the metabolism of THC! (Mechoulam et al., 1976).

For about two decades after the isolation of THC numerous groups, including ours, worked on the pharmacology of cannabinoids. The major contribution by my group was the discovery that THC activity is stereospecific, which indicated that apparently THC acts on a biological entity—be it an enzyme or a receptor (Mechoulam et al., 1987, 1988). Indeed, in the mid 1980s Allyn Howlett's group reported the existence of a receptor (Devane et al., 1988). As receptors obviously exist for activation by endogenous ligands and not by exogenous plant materials, we went ahead looking for such agonists. While we did not believe that they would resemble plant cannabinoids in their structure, we assumed that they should be—like the plant cannabinoids—lipid molecules. Hence the techniques we used were those followed for lipids. Bill Devane, who had just taken his PhD degree with Allyn Howlett and had joined my group as a post doc, took this project upon himself. The basic idea was to prepare a potent radiolabelled receptor ligand, bind it to Howlett's receptor (later named the CB₁ receptor) and then try to displace it with lipid brain fractions. Such fractions were to be purified, ultimately leading to a pure brain constituent—an endogenous receptor ligand. The first step was surprisingly easy. We reduced the highly potent (−)-11-hydroxy-THC-dimethylheptyl (HU-210), which we had synthesised a few years previously, to obtain an even more potent (−)-11-hydroxy-hexahydrocannabinol (Figure 1.2) (Devane et al., 1992a). It is presumably still the most potent cannabinoid known. Then this reduction reaction was repeated with tritium and the tritiated material was bound to the receptor found in pig brain. We decided to use pig brains as we understood that pig biochemistry is close to human biochemistry. At this point we were joined by Lumir Hanus, a post doc from Brno in the Czech state. Devane and Hanus extracted the brains with petroleum ether and indeed obtained active fractions by silica gel chromatography. However, as soon as active fractions were purified, they started to lose their activity. We know now that this was due to the lack of stability of the endogenous cannabinoid ligand. Ultimately we had a miniscule amount of material which seemed pure and we succeeded in obtaining NMR and mass spectra, which led to the correct structure (Devane et al., 1992b). We named it anandamide and synthesised it. In its receptor binding and initial pharmacological activity it paralleled THC (Fride and Mechoulam, 1993; Vogel et al., 1993; Smith et al., 1994). Later we identified in intestines a second major endogenous cannabinoid, 2-arachidonoylglycerol (2-AG) (Mechoulam et al., 1995). For structures of these endocannabinoids and related endogenous molecules, see Figure 1.3.

Figure 1.2 Preparation of labelled ligand used for isolation of anandamide

Figure 1.3 Endocannabinoids and related endogenous molecules

Over the next few years we investigated the structure–activity relationships of the endoc...

Table of contents

• Cover
• Title Page
• Copyright
• Dedication
• In memoriam
• List of Contributors
• Preface
• Chapter 1: Looking ahead after 50 years of research on cannabinoids
• Chapter 2: Cannabinoid receptor intracellular signalling: The long journey from binding sites to biological effects
• Chapter 3: Endocannabinoid biochemistry: What do we know after 50 years?
• Chapter 4: Genetic dissection of the endocannabinoid system and how it changed our knowledge of cannabinoid pharmacology and mammalian physiology
• Chapter 5: Cannabinoids, endocannabinoids and stress
• Chapter 6: Cannabinoids and the brain: New hopes for new therapies
• Chapter 7: Potential therapeutic applications of cannabinoids in gastrointestinal and liver diseases: Focus on Δ9-tetrahydrocannabinol pharmacology
• Chapter 8: Fifty years of ‘cannabinoid research’ and the need for a new nomenclature
• Index
• End User License Agreement