## Molecular Pharmacology of Phytocannabinoids

Sarah E. Turner, Claire M. Williams, Leslie Iversen, and Benjamin J. Whalley

© Springer International Publishing Switzerland 2017
A.D. Kinghorn, H. Falk, S. Gibbons, J. Kobayashi (eds.),

Phytocannabinoids, Progress in the Chemistry of Organic Natural Products 103, 61-100.

DOI 10.1007/978-3-319-45541-9_3

### Contents

1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
2 Δ9-trans-Tetrahydrocannabinol . . . . . . . . . . . . . . . . . . . . . . . . . . .  . . . . . . . . . .  . . . . . . . . . . 63
2.1 Activity at Cannabinoid Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . .  . . . . . . . . . . . 64
2.2 Cannabinoid Receptor Independent Activity . . . . . . . . . . . . . . . . . .  . . . . . . . . . . . .  . . . . . 68
3 Δ9-Tetrahydrocannabivarin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  . 71
3.1 Activity at Cannabinoid Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . .  . . 71
3.2 Cannabinoid Receptor Independent Activity . . . . . . . . . . . . . . . . . . . . . . . . .  . . . . . . . . .. . 73
4 Cannabinol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . .  . .  . . 74
4.1 Activity at Cannabinoid Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . 74
4.2 Cannabinoid Receptor Independent Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . … . .. . 75
5 Cannabidiol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . .  . . 76
5.1 Activity at Cannabinoid Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . 76
5.2 Cannabinoid Receptor Independent Activity . . . . . . . . . . . . . . . . . . . . . . . . . .  . . . . . . .. . . 77
6 Cannabidivarin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . .. . . 83
6.1 Activity at Cannabinoid Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . 84
6.2 Cannabinoid Receptor Independent Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . 84
7 Cannabigerol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
7.1 Activity at Cannabinoid Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . 86
7.2 Cannabinoid Receptor Independent Activity . . . . . . . . . . . . . . . . . . . . . . . . . . .  . . . . . . . . 87

8 Cannabichromene . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
8.1 Activity at Cannabinoid Receptors . . . . . . . . . . . . . . . . . . . .  . . . . . . . . . . . . . . . . . . . . . . . . 88
8.2 Cannabinoid Receptor Independent Activity . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . 88
9 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . 91

### 1 Introduction

Cannabis sativa contains about 120 phytocannabinoids, which are the C21 terpenophenolic constituents making up approximately 24% of the total natural products of the plant [1]. To date, eleven different chemical classes of phytocannabinoids have been identified (Table 1). The Δ9-tetrahydrocannabinol (1) type class represents the largest proportion, comprising 17.3% of the total phytocannabinoid content, closely followed by the cannabigerol (6) type (see [1] for a detailed review of these different classes). The proportion of each chemical class in the cannabis plant is, however, dependent on the growing conditions, geographical location, plant processing methods, and plant variety or chemotype. Thus, these factors influencing the relative proportions of each phytocannabinoid type will additionally influence the pharmacological effects of whole cannabis extracts, either through a polypharmacological effect of the phytocannabinoids themselves, or through modulation of phytocannabinoid effects by the non cannabinoid content of the plant [2]. These variances are therefore important to take into account when assessing the effects of whole cannabis plant extracts. In this chapter, focus will be made on the seven individual phytocannabinoids that have been the most thoroughly studied.

Phytocannabinoids have been of recreational, therapeutic, and other interest for thousands of years [3, 4]. Elucidation of the structure of the main phytocannabinoid obtained from cannabis, 1 [5], was reported in 1971. This discovery paved the way for further research that ultimately led to the discovery of the cannabinoid receptors, CB1 [6], which predominates in the central nervous system, and the principally peripheral cannabinoid receptor, CB2 [5]. The mammalian endocannabinoid system was then discovered [6], including the endogenous cannabinoid receptor ligands arachidonylethanolamide (AEA) and 2-arachidonylglycerol (2-AG) [7–9]. The psychotropic effect of 1, mediated by its partial agonist activity at CB1 receptors, has limited the extent of its use medicinally and it was removed from the British Pharmacopeia in 1971, and was declared of no medical benefit and placed under control in the Misuse of Drugs Act 1971 of the United Kingdom [10]. Despite this, patient-led self-medication campaigns claimed various therapeutic benefits, such as control of pain and emesis [11–15], control of seizures [16–21], and antiinflammatory properties [17, 22], among others. This drove further investigation, leading to some licensed medications containing 1 being now available, such as Sativex®, which is used for the treatment of spasticity associated with multiple sclerosis. Although 1 also exerts some effects through non-CB receptor targets, the absence of psychotropic effects associated with the other phytocannabinoids present in cannabis has driven research into their discrete pharmacology and molecular targets that lie outside of the endocannabinoid system.

Over the years, a variety of molecular targets for plant cannabinoids outside the endocannabinoid system have been identified, such as ion channels, non-CB1 or CB2 G-protein coupled receptors, enzymes, and transporters. In this chapter, an overview of the molecular pharmacology of phytocannabinoids is presented, describing both targets within the endocannabinoid system and a wide range of other molecular targets. Since ca. 120 phytocannabinoids have now been identified and many have, as yet, poorly defined or unknown pharmacological profiles, particular focus is paid to phytocannabinoids that: (a) are reported to exert a behavioral effect in animal models or clinical reports, and (b) exert effects via specific molecular targets at submicromolar to low micromolar concentrations, which can realistically be achieved in vivo due to the lipophilic nature of these compounds [23].

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