Cannabinomimetric Lipids : From Natural Extract to Artificial Synthesis

Ya-Ru Gao, Yong-Qiang Wang

Natural Products and Bioprospecting, 2018, 8, 1–21

doi : 10.1007/s13659-017-0151-9

Abstract

Endocannabinoid system is related with various physiological and cognitive processes including fertility, pregnancy, during pre- and postnatal development, pain-sensation, mood, appetite, and memory. In the latest decades, an important milestone concerning the endocannabinoid system was the discovery of the existence of the cannabinoid receptors CB1 and CB2. Anandamide was the first reported endogenous metabolite, which adjusted the release of some neurotransmitters through binding to the CB1 or CB2 receptors. Then a series of cannabinomimetric lipids were extracted from marine organisms, which possessed similar structure with anandamide. This review will provide a short account about cannabinomimetric lipids for their extraction and synthesis.

Keywords : Endocannabinoid, Cannabinoid receptors, Cannabinomimetric lipids

1 Introduction

In the past decades, pharmacologists devoted more interest to the study of endocannabinoid system due to its relation with various physiological and cognitive processes including fertility, pregnancy, during pre- and postnatal development, pain-sensation, mood, appetite, and memory [1]. Originally, the endocannabinoid system was discovered while scientists tried to understand the physical and psychological effects of cannabis, thereby named it the endocannabinoid system for this reason. An important milestone concerning the endocannabinoid system was the discovery of the existence of the cannabinoid receptors (CB1 and CB2) in central and peripheral mammalian tissues [2–5]. Both receptors CB1 and CB2 belong to the large family of G-protein-coupled receptors (GPCR). CB1 receptor exhibits a widespread distribution in the mammalian brain and are responsible for the psychological and anticonvulsive effects produced by marijuana [2–5], while CB2 receptor is most abundant in the immune and hematopoietic system and is involved in the anti-inflammatory and possibly other therapeutic effects of cannabis [4, 5]. The discovery of cannabinoid receptors (CB1 and CB2) has launched the quest for endogenous ligands of these receptors. Based on the assumption that the endogenous cannabinoid ligand was a lipid soluble compound, a lipid derivative was first isolated from chloroform– methanol extracts of porcine brain and christened anandamide by Mechoulam et al. in 1992 (Fig. 1) [6]. This endogenous metabolite bound to both CB1 and CB2 receptors and was found in nearly all tissues in a wide range of animals [7]. Then a series of alkyl amides were extracted from marine organisms, which resembled structurally some aspects of anandamide and had been termed cannabimimetic lipids. In the biological activity tests, they showed the ability to bind and activate at least one cannabinoid receptor [8]. This review will provide a short account of cannabinomimetric lipids for their natural extract and artificial synthesis.

2 Extraction and Biological Activities (Fig. 2)

2.1 Grenadamide

Grenadamide was isolated from the organic extract of a Grenada collection of the marine cyanobacterium Lyngbya majuscula by Gerwick et al. in 1998. It exhibited brine shrimp toxicity (LD50 = 5 lg/mL) and modest cannabinoid receptor binding activity (Ki = 4.7 lM) [9]. Gerwick et al. verified the structure and the relative stereochemistry of grenadamide, which was a trans-cyclopropyl-containing fatty acid-derived metabolite.

2.2 Mooreamide A

Mooreamide A was extracted from cyanobacterium Moorea bouillonii by Gerwick et al. from Papua New Guinea, and showed strong and selective affinity to CB1 ligand [10].

2.3 Serinolamides

Serinolamide A was isolated from marine cyanobacteria Lyngbya majuscule collected in Papua New Guineal. It displayed a moderate agonist effect and selectivity for the CB1 cannabinoid receptor [11]. Serinolamide B, a closely related analogue of serinolamide A, was isolated from a Lyngbya sample from the piti Bomb Holes in Guam by Luesch et al. [12]. It showed moderate affinities to both CB1 and CB2, while exhibited a higher selectivity for CB2 (Ki = 5.2 lm) over CB1 (Ki = 16.4 lm)

2.4 Semiplenamides

Semiplenamides A to G were isolated from the marine cyanobacterium Lyngbya semiplena collected from Papua New Guinea by Gerwick et al. [13]. In the test of their affinity to cannabinoid receptors of the rat brain membranes, only semiplenamides A, B and G worked. In the test of fatty acid amide hydrolase (FAAH), the semiplenamides A to G were not found appreciable inhibitory effect.

2.5 Malyngamides

Malyngamides include over 30 members, characterized by different N-substitution groups of amides. They were isolated from Marine cyanobacterium Lyngbya majuscule, and showed a wide range of biological activities, such as antifeedant activity, ichthyotoxicity, toxicity to other marine animals, cytotoxicity to cancer cells, anti-HIV, antileukemic, and anti-tumor activity [14–16]. The finding that malyngamide B possesses cannabimimetic properties provides new insight into the biological activities of malyngamides.

The extraction information of malyngamides was illustrated in Table 1.

Hermitamides resemble the malyngamide-type compound in structure and were still isolated from the marine marine cyanobacterium L. majuscula of other species of Gracilaria [17–19]. Hermitamides were evaluated for their biological activity in several systems. Hermitamides A (1) and B (2) showed LD50 values of 5 lM and 18 lM respectively in the brine shrimp (Artemia salina) toxicity assay, and showed IC50 values of 2.2 lM and 5.5 lM respectively to Neuro-2a neuroblastoma cells in tissue culture.

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Gao-Wang2018_Article_CannabinomimetricLipidsFromNat