Phytocannabinoids, Endocannabinoids and Synthetic Cannabinoids
The term "cannabinoid" has different meanings. Cannabinoids were originally defined as a group of C21 compounds uniquely produced by the cannabis plant. Subsequent development of synthetic cannabinoids and the discovery of natural cannabinoids in the body (“endocannabinoids”) has somewhat blurred this definition. The molecules derived from the plant itself are therefore now termed “phytocannabinoids”.
Synthetic cannabinoids are those which have been man-made.
Naturally occurring cannabis contains a group of chemical compounds not found in other plants known as cannabinoids. Different cannabinoids have been identified but the role and importance of many of these has yet to be fully understood. GW is researching a large number of cannabinoids, each of which has different effects and applications.
GW has unique access to an extensive library of “phytocannabinoids” through the breeding of unique “chemotypes” (plants characterised by their chemical content). Currently available cannabinoids include:
• D9-THC (Delta-9 Tetrahydrocannabinol)
• D8-THC (Delta-8 Tetrahydrocannabinol)
• THCA (Tetrahydrocannabinol – Acid)
• THCV (Tetrahydrocannabivarin)
• THCVA (Tetrahydrocannabivarin – Acid)
• CBD (Cannabidiol)
• CBDA (Cannabidiol - Acid)
• CBDV (Cannabidivarin) • CBDVA (Cannabidivarin - Acid)
• CBC (Cannabichromene)
• CBG (Cannabigerol)
• CBGA (Cannabigerol – Acid)
• CBGV (Cannabigerovarin)
• CBN (Cannabinol)
• CBNV (Cannabinovarin)
Of the cannabinoids listed above, only two cannabinoids have to date been well characterized – THC and CBD. Both THC and CBD have important pharmacology: THC has analgesic, anti-spasmodic, anti-tremor, anti-inflammatory, appetite stimulant and anti-emetic properties, whilst CBD has anti-inflammatory, anti-convulsant, anti-psychotic, anti-oxidant, neuroprotective and immunomodulatory effects. CBD is not intoxicating and indeed it has been postulated that the presence of CBD in cannabis may alleviate some of the potentially unwanted side-effects of THC. There is limited scientific information on the pharmacology and toxicology of the other cannabinoids.
GW believes that the beneficial therapeutic effects of cannabis derived medicines result from the interaction of different cannabinoids. In addition, GW believes that other components within the plant may also play a useful role.
The discovery of the cannabinoid receptors led to the demonstration of the existence of the body’s own natural cannabinoids (endocannabinoids), the most important of which are arachidonoyl-ethanolamide (anandamide), 2-arachidonoyl glycerol (2-AG) and arachidonyl glyceryl ether (noladin ether). This remains a highly dynamic field. There is evidence that anandamide can serve as a neuromodulator or neurotransmitter on its own or in conjunction with inactive precursors in what has been dubbed the “entourage effect”.
Cannabinoids are a group of terpenophenolic compounds present in Cannabis and occurring naturally in the nervous and immune systems of animals.
The broader definition of cannabinoids refers to a group of substances that are structurally related to tetrahydrocannabinol (THC) or that bind to cannabinoid receptors.
The chemical definition encompasses a variety of distinct chemical classes: the classical cannabinoids structurally related to THC, the nonclassical cannabinoids, the aminoalkylindoles, the eicosanoids related to the endocannabinoids, 1, quinolines and arylsulphonamides, and additional compounds that do not fall into these standard classes but bind to cannabinoid receptors.
The term ''cannabinoids'' also refers to a unique group of secondary metabolites found in the cannabis plant, which are responsible for the plant's peculiar pharmacological effects.
At the present time, there are three general types of cannabinoids: ''phytocannabinoids'' occur uniquely in the cannabis plant; ''endogenous cannabinoids'' are produced in the bodies of humans and other animals; and ''synthetic cannabinoids'' are similar compounds produced in a laboratory.
Cannabinoids are a class of chemical compounds which include the phytocannabinoids (oxygen-containing C21 aromatic hydrocarbon compounds found in the cannabis plant), and chemical compounds which mimic the actions of phytocannabinoids or have a similar structure (e.g. endocannabinoids, found in the nervous and immune systems of animals and that activate cannabinoid receptors). The most notable of the cannabinoids is ∆9-tetrahydrocannabinol (THC)—the primary psychoactive compound of cannabis.
Synthetic cannabinoids encompass a variety of distinct chemical classes: the classical cannabinoids structurally related to THC, the nonclassical cannabinoids including the aminoalkylindoles, 1,5-diarylpyrazoles, quinolines and arylsulphonamides, as well as eicosanoids related to the endocannabinoids.
“Mechoulam and Gaoni (1967) defined “cannabinoids” as a group of C21 terpenophenolic compounds uniquely produced by cannabis. The subsequent development of synthetic cannabinoids (e.g., HU-210) has blurred this definition, as has the discovery of endogenous cannabinoids (e.g., anandamide), defined as “endocannabinoids” by DiMarzo and Fontana (1995). Thus, Pate (1999) proposed the term “phytocannabinoids” to designate the C21 compounds produced by cannabis. There are many different cannabinoids and terpinoids present in a sample of cannabis, however only the main cannabinoids have been linked to pharmacological activity so far. The main cannabinoid types that are usually detected in each breeding strain or cultivar of cannabis are: THC, CBD, CBN, CBG and CBC. However, there can be an enormous variation in their quantitative ratios. THCV is now also considered to be a main cannabinoid.
In fresh cannabis plant material, THC is predominantly present in the form of its acidic precursor THC-acid (THCA). Under the influence of heat or storage, THCA can be converted into free THC. This statement about the acidic precursor is also true regarding CBD, CBG, CBC, and THCV as well. There is a test kit that not only reveals the cannabinoids in their neutral/active form, it reveals the acidic cannabinoids in their
natural form as well. Cannabinoids are enzymatically biosynthesized in the plant as their corresponding carboxylic acid forms (Taura et al., 2007). Neutral cannabinoids are formed via decarboxylation (loss of CO2) of the acidic cannabinoids during exposure to light, heat (e.g. smoking), or as a result of prolonged storage (Thakur et al., 2005). Cannabinol (CBN) is the most common oxidative degradation product of Δ9-THC found in aged cannabis (McPartland and Russo, 2001). Studies have determined that the acidic precursor of the neutral cannabinoids have important pharmacological properties as well. The therapeutic value of the acidic cannabinoid THCA as an immuno-modulating agent has only been discovered very
recently [Verhoeckx, 2006], and its effect has been patented. Examples like these show that the study of medicinal cannabis should include the whole array of cannabinoids present, as far as possible [McPartland, 2001]. The therapeutic potential of cannabinoids can be further clarified by pointing out the central physiological importance of the endocannabinoid system, and its homology to, and interaction with
the endorphin system. In addition to the role as modulator of food intake, the cannabinoid system is involved in several physiological functions and might be related to a general stress-recovery system. This variety of effects was concisely summarized by Di Marzo et al. , who stated that “cannabinoids help you feel less pain, control your movement, relax you, stimulate your appetite, forget (PTSS), sleep, and protect your neurons. The most commonly used method for analysis of cannabinoids is gas chromatography [Raharjo, 2004]. But because this method is based on heating of sample components, it converts acidic cannabinoids present in the sample into their decarboxylated counterparts. Therefore, gas chromatography analysis is not suitable for the determination of the authentic composition of the cannabinoids in the plant.
The primary constituent of cannabis, THC, is approved by the Food and Drug Administration (FDA) for oral administration as an appetite stimulant in the case of anorexia associated with weight loss in patients with HIV/AIDS. The other main cannabinoids have also been found to hold medicinal value.
CB1 receptors regulate pain perception, cardiovascular functions, gastrointestinal functions, steroid and hypothalamic hormone regulation, and reproduction. CB2 receptors seem to be involved in immuno-regulatory functions because of the relatively high level of expression in immune cells and tissues as well as
the effects observed by compounds that interact with CB2 receptors. The endocannabinoid system undergoes tissue specific changes in response to pathological conditions (Di Marzo and De
Petrocellis, 2006). The number of physiological functions mediated by the cannabinoid
receptor system makes it a highly attractive system to study for medicinal purposes both with the use of natural ligands and synthetically derived ligands. Numerous researchers cite the importance of the plethora of chemical components found in Cannabis and preparations derived from Cannabis and
the potential implications it may have on not only improving the therapeutic effect of
the drug for a particular condition but also for alleviating the potential side effects
caused by the main active ingredients in Cannabis such as THC [McPartland and Pruitt,
1999; McPartland and Russo, 2001].
Currently, (538) natural compounds were identified from this plant. Eighty five of these are identifed as cannabinoids, which are C21 compounds uniquely present in Cannabis sativa. There are ten main types of cannabinoids and fourteen different cannabinoid subtypes. Tetrahydrocannabinol (THC) is the principal psychoactive ingredient in cannabis, but it also has other effects. Cannabidiol (CBD) and cannabinol (CBN) are the other two most prevalent natural cannabinoids and have received the most study. All three are listed as ingredients in Sativex®, the only multi-cannabinoid medicine currently approved for marketing (only in Canada.)
Cannabinoids were first discovered in the 1940s, when CBD and CBN were identified. THC was not identified until 1964, but by that time cannabis had been removed from the pharmacopeiae of most countries, making further research on the plant difficult. There are three general types of cannabinoids:
1) Phytocannabinoids occur uniquely in the cannabis plant.
2) Endogenous cannabinoids are produced in the bodies of humans and other animals.
3) Synthetic cannabinoids are similar compounds produced in a laboratory. Forms of synthetic THC are available by prescription in a number of countries, including the US. In the US, synthetic THC is marketed as Marinol®.
Cannabinoids refers to a group of substances that are structurally related to Tetrahydrocannabinol (THC) or that bind to cannabinoid receptors. The term cannabinoids also refers to a unique group of secondary metabolites found in the cannabis plant, which are responsible for the plant's peculiar pharmacological effects. The human body possesses specific binding sites on the surface of many cell types for cannabinoids, and our body produces several endocannabinoids, fatty acid derivatives that bind to these cannabinoid receptors (CB) and activate them. CB receptors and endocannabinoids together constitute the endocannabinoid system.
Cannabinoid receptors have been identified (CB1, and the CB2 receptor). They differ in signaling mechanisms and tissue distribution.
The cannabinoid receptor type 1, often abbreviated to CB1, is a G protein-coupled cannabinoid receptor located in the brain. It is activated by endocannabinoid neurotransmitters including anandamide and by the compound THC, found in the psychoactive drug cannabis.
CB1 receptors are thought to be the most widely expressed G protein-coupled receptors in the brain. This is key to endocannabinoid-mediated depolarization-induced suppression of inhibition, a very common form of short-term plasticity in which the depolarization of a single neuron induces a reduction in GABA-mediated neurotransmission. Endocannabinoids released from the depolarized neuron bind to CB1 receptors in the pre-synaptic neuron and cause a reduction in GABA release. Varying levels of CB1 expression can be detected in the olfactory bulb, cortical regions (neocortex, pyriform cortex, hippocampus, and amygdala), several parts of basal ganglia, thalamic and hypothalamic nuclei and other subcortical regions (e.g. the septal region), cerebellar cortex, and brainstem nuclei (e.g. the periaqueductal gray).
CB1 is expressed on several cell types of the pituitary gland, in the thyroid gland, and most likely in the adrenal gland. CB1 is also expressed in several cells relating to metabolism, such as fat cells, muscle cells, liver cells (and also in the endothelial cells, Kupffer cells and stellate cells of the liver), and in the digestive tract. It is also expressed in the lungs and the kidney.
CB1 is present on Leydig cells and human sperms. In females, it is present in the ovaries, oviducts myometrium, decidua and placenta. It is probably important also for the embryo.
In the liver, activation of the CB1 receptor is known to increase de novo lipogenesis. Activation of presynaptic CB1 receptors is also known to inhibit sympathetic innervation of blood vessels and contributes to the suppression of the neurogenic vasopressor response in septic shock.
Inhibition of gastrointestinal activity has been observed after administration of Δ9-THC, or of anandamide. This effect has been assumed to be CB1-mediated since the specific CB1 antagonist SR 141716A (Rimonabant) blocks the effect. Another report, however, suggests that inhibition of intestinal motility may also have a CB2-mediated component.
Cannabinoids are well known for their cardiovascular activity. Activation of peripheral CB1 receptors contributes to hemorrhagic and endotoxin-induced hypotension. Anandamide and 2-AG, produced by macrophages and platelets respectively, may mediate this effect.
Anandamide attenuates the early phase or the late phase of pain behavior produced by formalin-induced chemical damage. This effect is produced by interaction with CB1 (or CB1-like) receptors, located on peripheral endings of sensory neurons involved in pain transmission. Palmitoylethanolamide, which like anandamide is present in the skin, also exhibits peripheral antinociceptive activity during the late phase of pain behavior. Palmitoylethanolamide, however, does not bind to either CB1 or CB2. Its analgesic activity is blocked by the specific CB2 antagonist SR144528, though not by the specific CB1 antagonist SR141716A. Hence a CB2-like receptor was postulated.
CB1 selective antagonists are used for weight reduction and smoking cessation. A substantial number of antagonists of the CB1 receptor have been discovered and characterized. TM38837 has been developed as a CB1 receptor antagonist that is restricted to targeting only peripheral CB1 receptors.
Cannabinoid receptors are activated by cannabinoids, generated naturally inside the body (endocannabinoids) or introduced into the body as cannabis or a related synthetic compound. They are activated in a dose-dependent, stereoselective and pertussis toxin-sensitive manner.
After the receptor is engaged, multiple intracellular signal transduction pathways are activated. At first, it was thought that cannabinoid receptors mainly activated the G protein Gi, which inhibits the enzyme adenylate cyclase (and thereby the production of the second messenger molecule cyclic AMP), and positively influenced inwardly rectifying potassium channels (=Kir or IRK). However, a much more complex picture has appeared in different cell types, implicating other potassium ion channels, calcium channels, protein kinase A and C, Raf-1, ERK, JNK, p38, c-fos, c-jun and many more.
Cannabinoid receptor 2 (macrophage), also known as CB2 or CNR2, is a G protein-coupled receptor from the cannabinoid receptor family, which in humans is encoded by the CNR2 gene. It is closely related to the cannabinoid receptor 1 which is responsible for the psychoactive properties of tetrahydrocannabinol, the active principle of marijuana.
CB2 was cloned in 1993 by a research group from Cambridge looking for a second cannabinoid receptor which could explain the pharmacological properties of tetrahydrocannabinol, the active principle of marijuana
Like the CB1 receptors, CB2 receptors inhibit the activity of adenylyl cyclase through their Gi/Goα subunits. Through their Gβγ subunits, CB2 receptors are also known to be coupled to the MAPK/ERK pathway, a complex and highly conserved signal transduction pathway, which critically regulates a number of important cellular processes in both mature and developing tissues. Activation of the MAPK-ERK pathway by CB2 receptor agonists acting on the Gβγ receptor subunit ultimately results in changes in cell migrationas well as in an induction of the growth-related gene Zif268(also known as Krox-24, NGFI-A, and egr-1). The Zifi268 gene encodes a transcriptional regulator implicated in neuroplasticity and long term memory formation.
At present, there are five recognized cannabinoids which are produced endogenously throughout the body; these endocannabinoids include Arachidonoylethanolamine (anandamide), 2-arachidonoyl glycerol (2-AG), 2-arachidonyl glyceryl ether (noladin ether), virodhamine, as well as the recently-discovered N-arachidonoyl-dopamine (NADA). Many of these ligands appear to exhibit properties of functional selectivity at the CB2 receptor: 2-AG preferentially activates the MAPK-ERK pathway, while noladin preferentially inhibits adenylyl cyclase . Like noladin, the synthetic ligand CP-55,940 has also been shown to preferentially inhibit adenylyl cyclase in CB2 receptors. Similar ligand-specific signaling has also been demonstrated in the CB1 receptor. Together, these results support the emerging concept of agonist-directed trafficking at the cannabinoid receptors.
The CB2 receptor is encoded by the CNR2 gene. Approximately 360 amino acids comprise the human CB2 receptor, making it somewhat shorter than the 473 amino acid long CB1 receptor. As is commonly seen in G protein-coupled receptors, the CB2 receptor has seven transmembrane spanning domains. The CB2 receptor also contains a glycosylated N-terminus as well as an intracellular C-terminus. The C-terminus of CB2 receptors appears to play a critical role in the regulation of ligand-induced receptor desensitization and downregulation; as a result of these processes, the cell may become less responsive to particular ligands.
The human CB1 and the CB2 receptors share approximately 44% amino acid similarity.
Initial investigation of CB2 receptor expression patterns focused on the presence of CB2 receptors in the peripheral tissues of the immune system. For instance, CB2 receptor mRNA was found throughout the immune tissues of the spleen, tonsils and thymus gland. Northern blot analysis further indicates the expression of the CNR2 gene in immune tissues. These receptors were primarily localized on immune cells such as monocytes, macrophages, B-cells, and T-cells. Further investigation into the expression patterns of the CB2 receptors revealed that CB2 receptor gene transcripts are also widely distributed throughout the brain. The CB2 receptors are found primarily on microglia(the immune cells of the CNS) and not neurons, however. CB2 receptors are also found throughout the gastrointestinal system, where they modulate intestinal inflammatory response. Thus, CB2 receptor agonists are a potential therapeutic target for inflammatory bowel diseases, such as Crohn’s disease and ulcerative colitis.
Primary research on the functioning of the CB2 receptor has focused on the receptor's effects on the immunological activity of leukocytes. Through their inhibition of adenylyl cyclase via their Gi/Goα subunits, CB2 receptor agonists cause a reduction in the intracellular levels of cyclic adenosine monophosphate (cAMP). Although the exact role of the cAMP cascade in the regulation of immune responses is currently under debate, laboratories have previously demonstrated that inhibition of adenylyl cyclase by CB2 receptor agonists results in a reduction in the transcription factor CREB (cAMP response element binding protein) binding to DNA; this in turn causes changes in the expression of critical immunoregulatory genes, and ultimately a suppression of immune function. Thus, CB2 agonists may also be useful for treatment of inflammation and pain, and in particular (neuropathic pain).
CB2 receptors may have possible therapeutic roles in the treatment of neurodegenerative disorders.
Changes in endocannabinoid levels and/or CB2 receptor expressions have been reported in almost all diseases affecting humans, ranging from cardiovascular, gastrointestinal, liver, kidney, neurodegenerative, psychiatric, bone, skin, autoimmune, lung disorders to pain and cancer, and modulating CB2 receptor activity by either selective CB2 receptor agonists or inverse agonists/antagonists (depending on the disease and its stage) hold unique therapeutic potential in these pathologies.
Type Skeleton Cyclization
Phytocannabinoids, also called natural cannabinoids, herbal cannabinoids, and classical cannabinoids, are only known to occur naturally in significant quantity in the cannabis plant, and are concentrated in a viscous resin that is produced in glandular structures known as trichomes. In addition to cannabinoids, the resin is rich in terpenes, which are largely responsible for the odor of the cannabis plant.
Phytocannabinoids are nearly insoluble in water but are soluble in lipids, alcohols, and other non-polar organic solvents. However, as phenols, they form more water-soluble phenolate salts under strongly alkaline conditions.
All-natural cannabinoids are derived from their respective 2-carboxylic acids (2-COOH) by decarboxylation (catalyzed by heat, light, or alkaline conditions).
At least eighty five cannabinoids have been isolated from the cannabis plant. All classes derive from cannabigerol-type compounds and differ mainly in the way this precursor is cyclized.
Tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabinol (CBN) are the most prevalent natural cannabinoids and have received the most study. Other common cannabinoids are listed below:
CBGM Cannabigerol Monoethyl Ether
Tetrahydrocannabinol (THC) is the primary psychoactive component of the plant. It appears to ease moderate pain (analgesic) and to be neuro-protective. THC has approximately equal affinity for the CB1 and CB2 receptors.
Delta-9-Tetrahydrocannabinol (Δ9-THC, THC) and delta-8-tetrahydrocannabinol (Δ8-THC), mimic the action of anandamide, a neurotransmitter produced naturally in the body. The (THC’s) produce the high associated with cannabis by binding to the CB1 cannabinoid receptors in the brain.
Cannabidiol (CBD) is not particularly psychoactive in and of itself, and was thought not to affect the psychoactivity of THC. However, recent evidence shows that smokers of cannabis with a higher CBD/THC ratio were less likely to experience schizophrenia-like symptoms. This is supported by psychological tests, in which participants experience less intense psychotic-like effects when intravenous THC was co-administered with CBD (as measured with a PANSS test). Cannabidiol has no affinity for CB1 and CB2 receptors but acts as an indirect antagonist of cannabinoid agonists. Recently it was found to be an antagonist at the putative new cannabinoid receptor, GPR55, a GPCR expressed in the caudate nucleus and putamen. Cannabidiol has also been shown to act as a 5-HT1A receptor agonist, an action which is involved in its antidepressant, anxiolytic, and neuroprotective effects.
It appears to relieve convulsion, inflammation, anxiety, and nausea. CBD has a greater affinity for the CB2 receptor than for the CB1 receptor.
CBD shares a precursor with THC and is the main cannabinoid in low-THC Cannabis strains. CBD apparently plays a role in preventing the short-term memory loss associated with THC in mammals.
Cannabinol (CBN) is the primary product of THC degradation, and there is usually little of it in a fresh plant. CBN content increases as THC degrades in storage, and with exposure to light and air. It is only mildly psychoactive. Its affinity to the CB2 receptor is higher than for the CB1 receptor.
Cannabigerol (CBG) is non-psychotomimetic but still affects the overall effects of Cannabis. It acts as an α2-adrenergic receptor agonist, 5-HT1A receptor antagonist, and CB1 receptor antagonist. It also binds to the CB2 receptor.
Tetrahydrocannabivarin (THCV) is prevalent in certain South African and Southeast Asian strains of Cannabis. It is an antagonist of THC at CB1 receptors and attenuates the psychoactive effects of THC.
Cannabichromene (CBC) is non-psychoactive and does not affect the psychoactivity of THC .
In addition, each of the compounds above may be in different forms depending on the position of the double bond in the alicyclic carbon ring. There is potential for confusion because there are different numbering systems used to describe the position of this double bond. Under the dibenzopyran numbering system widely used today, the major form of THC is called Δ9-THC, while the minor form is called Δ8-THC. Under the alternate terpene numbering system, these same compounds are called Δ1-THC and Δ6-THC, respectively.
Most herbal cannabinoid compounds are 21-carbon compounds. However, some do not follow this rule, primarily because of variation in the length of the side-chain attached to the aromatic ring. In THC, CBD, and CBN, this side-chain is a pentyl (5-carbon) chain. In the most common homologue, the pentyl chain is replaced with a propyl (3-carbon) chain. Cannabinoids with the propyl side-chain are named using the suffix varin, and are designated, for example, THCV, CBDV, or CBNV.
Cannabis plants can exhibit wide variation in the quantity and type of cannabinoids they produce. The mixture of cannabinoids produced by a plant are known as the plant's cannabinoid profile. Scientists have used “selective breeding” to control the genetics of plants and modify the cannabinoid profile. For example, strains used as fiber (commonly called hemp) are bred such that they are low in psychoactive chemicals like THC. Strains used in medicine are often bred for high CBD content, and strains used for recreational purposes are usually bred for high THC content or for a specific chemical balance.
Quantitative analysis of a plant's cannabinoid profile is usually determined by gas chromatography (GC), or more reliably by gas chromatography combined with mass spectrometry (GC/MS). Liquid chromatography (LC) techniques are also possible, although these are often only semi-quantitative or qualitative. There have been systematic attempts to monitor the cannabinoid profile of cannabis over time, but their accuracy has been impeded by the illegal status of the plant in many countries.
Cannabinoids can be administered by smoking, vaporizing, oral ingestion, transdermal patch, intravenous injection, sublingual absorption, or rectal suppository. Once in the body, most cannabinoids are metabolized in the liver, especially by cytochrome P450 mixed-function oxidases, mainly CYP 2C9. Thus supplementing with CYP 2C9 inhibitors leads to extended intoxication.
Some cannabinoids are stored in fat in addition to being metabolized in liver. Δ9-THC is metabolized to 11-hydroxy-Δ9-THC, which is then metabolized to 9-carboxy-THC. Some cannabis metabolites can be detected in the body several weeks after administration. These metabolites are the chemicals recognized by common antibody-based "drug tests"; in the case of THC et al., these loads do not represent intoxication (compare to ethanol breath tests which measure instantaneous blood alcohol levels) but an integration of past consumption over an approximately month-long window.
Cannabinoid production starts when an enzyme causes geranyl pyrophosphate and olivetolic acid to combine and form CBG. Next, CBG is independently converted to either CBD or CBC by two separate synthase enzymes. CBD is then enzymatically cyclized to THC. For the propyl homologues (THCV, CBDV and CBNV), there is a similar pathway that is based on CBGV.
Cannabinoids can be separated from the plant by extraction with organic solvents. Hydrocarbons and alcohols are often used as solvents. However, these solvents are flammable and many are toxic. Butane may be used, which evaporates very quickly. Supercritical solvent extraction with carbon dioxide is an alternative technique. Although this process requires high pressures (73 atmospheres or more), there is minimal risk of fire or toxicity. Solvent removal is simple and efficient, and extract quality can be well-controlled. Once extracted, cannabinoid blends can be separated into individual components using wiped film vacuum distillation or other distillation techniques. However, to produce high purity cannabinoids, chemical synthesis or semisynthesis is generally required.
Cannabinoids were first discovered in the 1940s, when CBD and CBN were identified. The structure of THC was first determined in 1964.
Due to molecular similarity and ease of synthetic conversion, CBD was originally believed to be a natural precursor to THC. However, it is now known that CBD and THC are produced independently in the cannabis plant.
Anandamide, an endogenous ligand of CB1 and CB2
Endocannabinoids are substances produced from within the body that activate cannabinoid receptors. After the discovery of the first cannabinoid receptor in 1988, scientists began searching for an endogenous ligand for the receptor.
Arachidonoylethanolamine (Anandamide or AEA)
In 1992, in Raphael Mechoulam's Israeli lab, the first such compound was identified as arachidonoyl ethanolamine and named anandamide, a name derived from the Sanskrit word for bliss. Anandamide is derived from the essential fatty acid arachidonic acid. It has a pharmacology similar to THC, although its chemical structure is different. Anandamide binds to the central (CB1) and, to a lesser extent, peripheral (CB2) cannabinoid receptors, where it acts as a partial agonist. Anandamide is about as potent as THC at the CB1 receptor. It can be found in nearly all tissues in a wide range of animals.
Two analogs of anandamide, (7,10,13,16-docosatetraenoylethanolamide and homo-γ-linolenoylethanolamine), have similar pharmacology. All of these are members of a family of signaling lipids called N-acylethanolamides, which also includes the noncannabimimetic palmitoylethanolamide and oleoylethanolamine, which possess anti-inflammatory and orexigenic effects, respectively. Many N-acylethanolamines have also been identified in plant seeds and in molluscs.
2-arachidonoyl glycerol (2-AG)
Another endocannabinoid, 2-arachidonoyl glycerol, binds to both the CB1 and CB2 receptors with similar affinity, acting as a full agonist at both. 2-AG is present at significantly higher concentrations in the brain than anandamide, and there is some controversy over whether 2-AG rather than anandamide is chiefly responsible for endocannabinoid signalling in vivo. In particular, one in vitro study suggests that 2-AG is capable of stimulating higher G-protein activation than anandamide, although the physiological implications of this finding are not yet known.
2-arachidonyl glyceryl ether (noladin ether)
In 2001, a third, ether-type endocannabinoid, 2-arachidonyl glyceryl ether (noladin ether), was isolated from porcine brain. Prior to this discovery, it had been synthesized as a stable analog of 2-AG; indeed, some controversy remains over its classification as an endocannabinoid, as another group failed to detect the substance at "any appreciable amount" in the brains of several different mammalian species. It binds to the CB1 cannabinoid receptor (Ki = 21.2 nmol/L) and causes sedation, hypothermia, intestinal immobility, and mild anti-nociception in mice. It binds primarily to the CB1 receptor, and only weakly to the CB2 receptor.
Discovered in 2000, NADA preferentially binds to the CB1 receptor. Like anandamide, NADA is also an agonist for the vanilloid receptor subtype 1 (TRPV1), a member of the vanilloid receptor family.
A fifth endocannabinoid, virodhamine, or O-arachidonoyl-ethanolamine (OAE), was discovered in June 2002. Although it is a full agonist at CB2 and a partial agonist at CB1, it behaves as a CB1 antagonist in vivo. In rats, virodhamine was found to be present at comparable or slightly lower concentrations than anandamide in the brain, but (2 to 9) fold higher concentrations peripherally.
Endocannabinoids serve as intercellular 'lipid messengers', signaling molecules that are released from one cell and activating the cannabinoid receptors present on other nearby cells. Although in this intercellular signaling role they are similar to the well-known monoamine neurotransmitters, such as acetylcholine and dopamine, endocannabinoids differ in numerous ways from them. For instance, they use retrograde signaling. Furthermore, endocannabinoids are lipophilic molecules that are not very soluble in water. They are not stored in vesicles, and exist as integral constituents of the membrane bi-layers that make up cells. They are believed to be synthesized 'on-demand' rather than made and stored for later use. The mechanisms and enzymes underlying the biosynthesis of endocannabinoids remain elusive and continue to be an area of active research.
The endocannabinoid 2-AG has been found in bovine and human maternal milk.
Conventional neurotransmitters are released from a ‘presynaptic’ cell and activate appropriate receptors on a ‘postsynaptic’ cell, where presynaptic and postsynaptic designate the sending and receiving sides of a synapse, respectively. Endocannabinoids, on the other hand, are described as retrograde transmitters because they most commonly travel ‘backwards’ against the usual synaptic transmitter flow. They are, in effect, released from the postsynaptic cell and act on the presynaptic cell, where the target receptors are densely concentrated on axonal terminals in the zones from which conventional neurotransmitters are released. Activation of cannabinoid receptors temporarily reduces the amount of conventional neurotransmitter released. This endocannabinoid mediated system permits the postsynaptic cell to control its own incoming synaptic traffic. The ultimate effect on the endocannabinoid-releasing cell depends on the nature of the conventional transmitter being controlled. For instance, when the release of the inhibitory transmitter GABA is reduced, the net effect is an increase in the excitability of the endocannabinoid-releasing cell. On the converse, when release of the excitatory neurotransmitter glutamate is reduced, the net effect is a decrease in the excitability of the endocannabinoid-releasing cell.
Endocannabinoids are hydrophobic molecules. They cannot travel unaided for long distances in the aqueous medium surrounding the cells from which they are released, and therefore act locally on nearby target cells. Hence, although emanating diffusely from their source cells, they have much more restricted spheres of influence than do hormones, which can affect cells throughout the body.
Endocannabinoids constitute a versatile system for affecting neuronal network properties in the nervous system.
The current understanding recognizes the role that endocannabinoids play in almost every major life function in the human body.
Historically, laboratory synthesis of cannabinoids were often based on the structure of herbal cannabinoids, and a large number of analogs have been produced and tested, especially in a group led by Roger Adams as early as 1941 and later in a group led by Raphael Mechoulam. Newer compounds are no longer related to natural cannabinoids or are based on the structure of the endogenous cannabinoids.
Synthetic cannabinoids are particularly useful in experiments to determine the relationship between the structure and activity of cannabinoid compounds, by making systematic, incremental modifications of cannabinoid molecules.
Medications containing natural or synthetic cannabinoids or cannabinoid analogs:
Dronabinol (Marinol), is Δ9-tetrahydrocannabinol (THC), used as an appetite stimulant, anti-emetic, and analgesic
Nabilone (Cesamet), a synthetic cannabinoid and an analog of Marinol. It is Schedule II unlike Marinol, which is Schedule III
Sativex, a cannabinoid extract oral spray containing THC, CBD, and other cannabinoids used for neuropathic pain and spasticity in twenty two countries including England, Canada and Spain. Sativex develops whole-plant cannabinoid medicines
Rimonabant (SR141716), a selective cannabinoid (CB1) receptor inverse agonist used as an anti-obesity drug under the proprietary name Acomplia. It is also used for smoking cessation
JWH-018, is a potent synthetic cannabinoid agonist discovered by Dr. John W. Huffman at Clemson University. It is increasingly being sold in legal smoke blends collectively known as "spice". Several countries and states have moved to ban it legally.
CP-55940, produced in 1974, this synthetic cannabinoid receptor agonist is many times more potent than THC.
HU-210, about 100 times as potent as THC.
HU-331, a potential anti-cancer drug derived from cannabidiol that specifically inhibits topoisomerase II.
SR144528, a CB2 receptor antagonist.
WIN 55,212-2, a potent cannabinoid receptor agonist.
JWH-133, a potent selective CB2 receptor agonist.
Levonantradol (Nantrodolum), an anti-emetic and analgesic but not currently in use in medicine
TABLE OF NATURAL CANNABINOIDS
Cannabinerolic acid A
Cannabigerolic acid A
Cannabigerolic acid A
Cannabigerovarinic acid A
(±)-Cannabichromenic acid A
cannabinolic acid A
cannabinolic acid B
A and/or B
Δ9-THCA-C4 A and/or B
cannabivarinic acid A
A and/or B
Δ9-THCOA-C1 A and/or B
Cannabinolic acid A
Cannabinol methyl ether
Cannabidiolic acid A
CBDA-C5 9-OH-CBT-C5 ester
Cannabielsoic acid A
Cannabielsoic acid B
C3-Cannabielsoic acid B
Cannabicyclolic acid A
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