Cannabinoid receptor type 1 (CB
1), also known as cannabinoid receptor 1, is a
G protein-coupled
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
cannabinoid receptor
Cannabinoid receptors, located throughout the body, are part of the endocannabinoid system a class of cell membrane receptors in the G protein-coupled receptor superfamily. As is typical of G protein-coupled receptors, the cannabinoid recep ...
that in humans is encoded by the ''CNR1''
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
.
The human CB
1 receptor is
expressed in the
peripheral nervous system
The peripheral nervous system (PNS) is one of two components that make up the nervous system of bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside the brain ...
and
central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...
.
It is activated by:
endocannabinoids
Cannabinoids () are several structural classes of compounds found in the cannabis plant primarily and most animal organisms (although insects lack such receptors) or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tet ...
, a group of
retrograde neurotransmitters that include
anandamide
Anandamide (ANA), also known as ''N''-arachidonoylethanolamine (AEA), is a fatty acid neurotransmitter. Anandamide was the first endocannabinoid to be discovered: it participates in the body's endocannabinoid system by binding to cannabinoid r ...
and
2-arachidonoylglycerol
2-Arachidonoylglycerol (2-AG) is an endocannabinoid, an endogenous agonist of the CB1 receptor and the primary endogenous ligand for the CB2 receptor. It is an ester formed from the omega-6 fatty acid arachidonic acid and glycerol. It is present ...
(2-AG); plant
phytocannabinoid
Cannabinoids () are several structural classes of compounds found in the cannabis plant primarily and most animal organisms (although insects lack such receptors) or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tet ...
s, such as the compound
THC
Tetrahydrocannabinol (THC) is the principal psychoactive constituent of cannabis and one of at least 113 total cannabinoids identified on the plant. Although the chemical formula for THC (C21H30O2) describes multiple isomers, the term ''THC' ...
which is an active ingredient of the
psychoactive drug
A psychoactive drug, psychopharmaceutical, psychoactive agent or psychotropic drug is a chemical substance, that changes functions of the nervous system, and results in alterations in perception, mood, consciousness, cognition or behavior. ...
cannabis
''Cannabis'' () is a genus of flowering plants in the family Cannabaceae. The number of species within the genus is disputed. Three species may be recognized: '' Cannabis sativa'', '' C. indica'', and '' C. ruderalis''. Alternative ...
; and,
synthetic analogs of THC. CB1 is
antagonized by the phytocannabinoid
tetrahydrocannabivarin
Tetrahydrocannabivarin (THCV, THV, O-4394, GWP42004) is a homologue of tetrahydrocannabinol (THC) having a propyl (3-carbon) side chain instead of a pentyl (5-carbon) group on the molecule, which makes it produce very different effects from THC. ...
(THCV).
The primary
endogenous agonist
In pharmacology, an endogenous agonist for a particular receptor is a compound naturally produced by the body which binds to and activates that receptor. For example, the primary endogenous agonist for serotonin receptors is serotonin, and the ...
of the human CB
1 receptor is
anandamide
Anandamide (ANA), also known as ''N''-arachidonoylethanolamine (AEA), is a fatty acid neurotransmitter. Anandamide was the first endocannabinoid to be discovered: it participates in the body's endocannabinoid system by binding to cannabinoid r ...
.
Structure
The CB
1 receptor shares the structure characteristic of all G-protein-coupled receptors, possessing seven transmembrane domains connected by three extracellular and three intracellular loops, an extracellular N-terminal tail, and an intracellular C-terminal tail.
The receptor may exist as a
homodimer
In biochemistry, a protein dimer is a macromolecular complex formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ''dimer'' has ...
or form
heterodimers or other
GPCR oligomer
A GPCR oligomer is a protein complex that consists of a small number ( ''oligoi'' "a few", ''méros'' "part, piece, component") of G protein-coupled receptors (GPCRs). It is held together by covalent bonds or by intermolecular forces. The subun ...
s with different
classes of G-protein-coupled receptors. Observed heterodimers include A
2A–CB
1, CB
1–D
2, OX
1–CB
1, μOR–CB
1, while many more may only be stable enough to exist in vivo.
The CB
1 receptor possesses an
allosteric modulatory
binding site
In biochemistry and molecular biology, a binding site is a region on a macromolecule such as a protein that binds to another molecule with specificity. The binding partner of the macromolecule is often referred to as a ligand. Ligands may includ ...
.
Mechanism
The CB
1 receptor is a pre-synaptic
heteroreceptor A heteroreceptor is a receptor regulating the synthesis and/or the release of mediators other than its own ligand.
Heteroreceptors respond to neurotransmitters, neuromodulators, or neurohormones released from adjacent neurons or cells; they are o ...
that modulates neurotransmitter release when activated in a dose-dependent, stereoselective and
pertussis toxin
Pertussis toxin (PT) is a protein-based AB5-type exotoxin produced by the bacterium ''Bordetella pertussis'', which causes whooping cough. PT is involved in the colonization of the respiratory tract and the establishment of infection. Rese ...
-sensitive manner.
The CB
1 receptor is activated by
cannabinoids
Cannabinoids () are several structural classes of compounds found in the cannabis plant primarily and most animal organisms (although insects lack such receptors) or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tet ...
, generated naturally inside the body (
endocannabinoids
Cannabinoids () are several structural classes of compounds found in the cannabis plant primarily and most animal organisms (although insects lack such receptors) or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tet ...
) or introduced into the body as
cannabis
''Cannabis'' () is a genus of flowering plants in the family Cannabaceae. The number of species within the genus is disputed. Three species may be recognized: '' Cannabis sativa'', '' C. indica'', and '' C. ruderalis''. Alternative ...
or a related
synthetic compound.
Research suggests that the majority of CB
1 receptors are coupled through G
i/o proteins. Upon activation, CB
1 receptor exhibits its effects mainly through activation of
Gi, which decreases intracellular cAMP concentration by inhibiting its production
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
,
adenylate cyclase
Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction:
:A ...
, and increases
mitogen-activated protein kinase (MAP kinase) concentration. Alternatively, in some rare cases CB
1 receptor activation may be coupled to
Gs proteins, which stimulate
adenylate cyclase
Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction:
:A ...
.
cAMP is known to serve as a second messenger coupled to a variety of ion channels, including the positively influenced
inwardly rectifying potassium channels (=Kir or IRK),
and
calcium channels, which are activated by cAMP-dependent interaction with such molecules as
protein kinase A
In cell biology, protein kinase A (PKA) is a family of enzymes whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase (). PKA has several functions in the cell, including regulatio ...
(PKA),
protein kinase C (PKC),
Raf-1,
ERK,
JNK
c-Jun N-terminal kinases (JNKs), were originally identified as kinases that bind and phosphorylate c-Jun on Ser-63 and Ser-73 within its transcriptional activation domain. They belong to the mitogen-activated protein kinase family, and ar ...
,
p38,
c-fos,
c-jun, and others.
In terms of function, the inhibition of intracellular cAMP expression shortens the duration of pre-synaptic action potentials by prolonging the rectifying potassium A-type currents, which is normally inactivated upon phosphorylation by PKA. This inhibition grows more pronounced when considered with the effect of activated CB
1 receptors to limit calcium entry into the cell, which does not occur through cAMP but by a direct G-protein-mediated inhibition. As presynaptic calcium entry is a requirement for vesicle release, this function will decrease the transmitter that enters the synapse upon release.
The relative contribution of each of these two inhibitory mechanisms depends on the variance of ion channel expression by cell type.
The CB
1 receptor can also be
allosterically modulated by synthetic ligands
in a positive
and negative
manner. ''
In vivo
Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
'' exposure to
THC
Tetrahydrocannabinol (THC) is the principal psychoactive constituent of cannabis and one of at least 113 total cannabinoids identified on the plant. Although the chemical formula for THC (C21H30O2) describes multiple isomers, the term ''THC' ...
impairs
long-term potentiation
In neuroscience, long-term potentiation (LTP) is a persistent strengthening of synapses based on recent patterns of activity. These are patterns of synaptic activity that produce a long-lasting increase in signal transmission between two neurons ...
and leads to a reduction of phosphorylated
CREB
CREB-TF (CREB, cAMP response element-binding protein) is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the genes. CREB was first de ...
.
The signaling properties of activated CB
1 are furthermore modified by the presence of
SGIP1, that hinders receptor internalization and decreases
ERK1/2 signalling while augmenting the interaction with
GRK3
G-protein-coupled receptor kinase 3 (GRK3) is an enzyme that in humans is encoded by the ''ADRBK2'' gene. GRK3 was initially called Beta-adrenergic receptor kinase 2 (βARK-2), and is a member of the G protein-coupled receptor kinase subfamily of ...
,
β-arrestin-2.
In summary, CB
1 receptor activity has been found to be coupled to certain ion channels, in the following manner:
* Positively to inwardly rectifying and A-type outward potassium channels.
* Negatively to D-type outward potassium channels
* Negatively to N-type and P/Q-type calcium channels.
Expression
The CB
1 receptor is encoded by the gene ''CNR1,''
located on human chromosome 6.
Two transcript variants encoding different isoforms have been described for this gene.
CNR1
orthologs
Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a sp ...
have been identified in most
mammals
Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur o ...
.
The CB
1 receptor is expressed pre-synaptically at both glutaminergic and GABAergic interneurons and, in effect, acts as a
neuromodulator
Neuromodulation is the physiological process by which a given neuron uses one or more chemicals to regulate diverse populations of neurons. Neuromodulators typically bind to metabotropic, G-protein coupled receptors (GPCRs) to initiate a second ...
to inhibit release of
glutamate and
GABA.
Repeated administration of receptor agonists may result in receptor internalization and/or a reduction in receptor protein signalling.
The
inverse agonist MK-9470
MK-9470 is a synthetic compound, which binds to the CB1 cannabinoid receptor
Cannabinoid receptors, located throughout the body, are part of the endocannabinoid system a class of cell membrane receptors in the G protein-coupled receptor s ...
makes it possible to produce ''in vivo'' images of the distribution of CB
1 receptors in the human brain with
positron emission tomography.
Brain
CB
1 receptors are expressed most densely in the central nervous system and are largely responsible for mediating the effects of cannabinoid binding in the brain. Endocannabinoids released by a depolarized neuron bind to CB
1 receptors on pre-synaptic glutamatergic and GABAergic neurons, resulting in a respective decrease in either glutamate or GABA release. Limiting glutamate release causes reduced excitation, while limiting GABA release suppresses inhibition, a common form of short-term
plasticity in which the depolarization of a single neuron induces a reduction in
GABA-mediated inhibition, in effect exciting the postsynaptic cell.
Varying levels of CB
1 expression can be detected in the
olfactory bulb
The olfactory bulb (Latin: ''bulbus olfactorius'') is a neural structure of the vertebrate forebrain involved in olfaction, the sense of smell. It sends olfactory information to be further processed in the amygdala, the orbitofrontal cortex ( ...
,
cortical regions (
neocortex,
pyriform cortex
The piriform cortex, or pyriform cortex, is a region in the brain, part of the rhinencephalon situated in the cerebrum. The function of the piriform cortex relates to the sense of smell.
Structure
The piriform cortex is part of the rhinencepha ...
,
hippocampus
The hippocampus (via Latin from Greek , ' seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, ...
, and
amygdala
The amygdala (; plural: amygdalae or amygdalas; also '; Latin from Greek, , ', 'almond', 'tonsil') is one of two almond-shaped clusters of nuclei located deep and medially within the temporal lobes of the brain's cerebrum in complex verte ...
), several parts of
basal ganglia
The basal ganglia (BG), or basal nuclei, are a group of subcortical nuclei, of varied origin, in the brains of vertebrates. In humans, and some primates, there are some differences, mainly in the division of the globus pallidus into an exter ...
,
thalamic and
hypothalamic nuclei, and other subcortical regions (e.g., the
septal region),
cerebellar cortex
The cerebellum (Latin for "little brain") is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as or even larger. In humans, the cerebe ...
, and
brainstem nuclei (e.g., the
periaqueductal gray
The periaqueductal gray (PAG, also known as the central gray) is a brain region that plays a critical role in autonomic function, motivated behavior and behavioural responses to threatening stimuli. PAG is also the primary control center for d ...
).
Hippocampal formation
CB
1 mRNA
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein.
mRNA is created during the ...
transcripts are abundant in
GABAergic interneurons of the
hippocampus
The hippocampus (via Latin from Greek , ' seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, ...
, indirectly reflecting the expression of these receptors and elucidating the established effect of cannabinoids on
memory
Memory is the faculty of the mind by which data or information is encoded, stored, and retrieved when needed. It is the retention of information over time for the purpose of influencing future action. If past events could not be remembered ...
. These receptors are densely located in
cornu ammonis
The hippocampus proper refers to the actual structure of the hippocampus which is made up of three regions or subfields. The subfields CA1, CA2, and CA3 use the initials of Hippocampus#Name, cornu Ammonis, an earlier name of the hippocampus.
St ...
pyramidal cells, which are known to release
glutamate. Cannabinoids suppress the induction of
LTP
LTP may refer to:
Biology and medicine
* Lateral tibial plateau, part of a leg bone
* Lipid transfer proteins, proteins found in plant tissues
* Long-term potentiation (neurophysiology), a long-lasting enhancement in signal transmission between ...
and
LTD in the hippocampus by inhibiting these glutamatergic neurons. By reducing the concentration of glutamate released below the threshold necessary to depolarize the postsynaptic receptor
NMDA
''N''-methyl--aspartic acid or ''N''-methyl--aspartate (NMDA) is an amino acid derivative that acts as a specific agonist at the NMDA receptor mimicking the action of glutamate, the neurotransmitter which normally acts at that receptor. Unlike ...
,
a receptor known to be directly related to the induction of LTP and LTD, cannabinoids are a crucial factor in the selectivity of memory.
These receptors are highly expressed by GABAergic interneurons as well as glutamatergic principal neurons. However, a higher density is found within GABAergic cells.
This means that, although synaptic strength/frequency, and thus potential to induce LTP, is lowered, net hippocampal activity is raised. In addition, CB
1 receptors in the hippocampus indirectly inhibit the release of
acetylcholine. This serves as the modulatory axis opposing GABA, decreasing neurotransmitter release. Cannabinoids also likely play an important role in the development of memory through their neonatal promotion of
myelin
Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be ...
formation, and thus the individual segregation of axons.
Basal ganglia
CB
1 receptors are expressed throughout the
basal ganglia
The basal ganglia (BG), or basal nuclei, are a group of subcortical nuclei, of varied origin, in the brains of vertebrates. In humans, and some primates, there are some differences, mainly in the division of the globus pallidus into an exter ...
and have well-established effects on movement in
rodents. As in the
hippocampus
The hippocampus (via Latin from Greek , ' seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, ...
, these receptors inhibit the release of
glutamate or
GABA transmitter, resulting in decreased excitation or reduced inhibition based on the cell they are expressed in. Consistent with the variable expression of both excitatory glutamate and inhibitory GABA interneurons in both the basal ganglia's direct and indirect motor loops,
synthetic cannabinoids are known to influence this system in a dose-dependent triphasic pattern. Decreased locomotor activity is seen at both higher and lower concentrations of applied
cannabinoids
Cannabinoids () are several structural classes of compounds found in the cannabis plant primarily and most animal organisms (although insects lack such receptors) or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tet ...
, whereas an enhancement of movement may occur upon moderate dosages.
However, these dose-dependent effects have been studied predominately in rodents, and the physiological basis for this triphasic pattern warrants future research in humans. Effects may vary based on the site of cannabinoid application, input from higher cortical centers, and whether drug application is unilateral or bilateral.
Cerebellum and neocortex
The role of the CB
1 receptor in the regulation of motor movements is complicated by the additional expression of this receptor in the
cerebellum and
neocortex, two regions associated with the coordination and initiation of movement. Research suggests that anandamide is synthesized by
Purkinje cells
Purkinje cells, or Purkinje neurons, are a class of GABAergic inhibitory neurons located in the cerebellum. They are named after their discoverer, Czech anatomist Jan Evangelista Purkyně, who characterized the cells in 1839.
Structure
T ...
and acts on presynaptic receptors to inhibit glutamate release from granule cells or
GABA release from the terminals of basket cells. In the neocortex, these receptors are concentrated on local interneurons in cerebral layers II-III and V-VI.
Compared to rat brains, humans express more CB
1 receptors in the cerebral cortex and amygdala and less in the cerebellum, which may help explain why motor function seems to be more compromised in rats than humans upon cannabinoid application.
Spine
Many of the documented analgesic effects of cannabinoids are based on the interaction of these compounds with CB
1 receptors on
spinal cord
The spinal cord is a long, thin, tubular structure made up of nervous tissue, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone). The backbone encloses the central canal of the sp ...
interneurons in the superficial levels of the
dorsal horn, known for its role in nociceptive processing. In particular, the CB
1 is heavily expressed in layers 1 and 2 of the spinal cord dorsal horn and in lamina 10 by the central canal. Dorsal root ganglion also express these receptors, which target a variety of peripheral terminals involved in nociception. Signals on this track are also transmitted to the
periaqueductal gray
The periaqueductal gray (PAG, also known as the central gray) is a brain region that plays a critical role in autonomic function, motivated behavior and behavioural responses to threatening stimuli. PAG is also the primary control center for d ...
(PAG) of the midbrain. Endogenous cannabinoids are believed to exhibit an analgesic effect on these receptors by limiting both GABA and glutamate of PAG cells that relate to nociceptive input processing, a hypothesis consistent with the finding that anandamide release in the PAG is increased in response to pain-triggering stimuli.
Other
CB
1 is expressed on several types of cell in
pituitary gland
In vertebrate anatomy, the pituitary gland, or hypophysis, is an endocrine gland, about the size of a chickpea and weighing, on average, in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain. The ...
,
thyroid gland, and possibly in the
adrenal gland
The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer cortex whic ...
.
CB
1 is also expressed in several cells relating to metabolism, such as
fat cells
Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through adipogenesis. I ...
,
muscle cells
A muscle cell is also known as a myocyte when referring to either a cardiac muscle cell (cardiomyocyte), or a smooth muscle cell as these are both small cells. A skeletal muscle cell is long and threadlike with many nuclei and is called a mus ...
,
liver cells
A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass.
These cells are involved in:
* Protein synthesis
* Protein storage
* Transformation of carbohydrates
* Synthesis of cholesterol, ...
(and also in the
endothelial cells
The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...
,
Kupffer cell
Kupffer cells, also known as stellate macrophages and Kupffer–Browicz cells, are specialized cells localized in the liver within the lumen of the liver sinusoids and are adhesive to their endothelial cells which make up the blood vessel walls. Ku ...
s and
stellate cells of the
liver
The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...
), and in the
digestive tract
The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...
.
It is also expressed in the
lungs
The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side ...
and the
kidney
The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blo ...
.
CB
1 is present on
Leydig cells
Leydig cells, also known as interstitial cells of the testes and interstitial cells of Leydig, are found adjacent to the seminiferous tubules in the testicle and produce testosterone in the presence of luteinizing hormone (LH). They are polyhedra ...
and human
sperms. In
females
Female (symbol: ♀) is the sex of an organism that produces the large non-motile ova (egg cells), the type of gamete (sex cell) that fuses with the male gamete during sexual reproduction.
A female has larger gametes than a male. Females ...
, it is present in the
ovaries
The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body. T ...
,
oviduct
The oviduct in mammals, is the passageway from an ovary. In human females this is more usually known as the Fallopian tube or uterine tube. The eggs travel along the oviduct. These eggs will either be fertilized by spermatozoa to become a zygote, o ...
s
myometrium
The myometrium is the middle layer of the uterine wall, consisting mainly of uterine smooth muscle cells (also called uterine myocytes) but also of supporting stromal and vascular tissue. Its main function is to induce uterine contractions.
Struc ...
,
decidua
The decidua is the modified mucosal lining of the uterus (that is, modified endometrium) that forms every month, in preparation for pregnancy. It is shed off each month when there is no fertilised egg to support. The decidua is under the influen ...
, and
placenta
The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate mate ...
. It has also been implicated in the proper development of the
embryo.
CB
1 is also expressed in the
retina
The retina (from la, rete "net") is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which then ...
. In the retina, they are expressed in the photoreceptors, inner plexiform, outer plexiform, bipolar cells, ganglion cells, and retinal pigment epithelium cells.
In the visual system, cannabinoids agonist induce a dose dependent modulation of calcium, chloride and potassium channels. This alters vertical transmission between photoreceptor, bipolar and ganglion cells. Altering vertical transmission in turn results in the way vision is perceived.
Use of antagonists
Selective CB
1 agonists may be used to isolate the effects of the receptor from the CB
2 receptor, as most cannabinoids and endocannabinoids bind to both receptor types.
CB1 selective antagonists are used for weight reduction and
smoking cessation
Smoking cessation, usually called quitting smoking or stopping smoking, is the process of discontinuing tobacco smoking. Tobacco smoke contains nicotine, which is addictive and can cause dependence. As a result, nicotine withdrawal often m ...
(see
Rimonabant
Rimonabant (also known as SR141716; trade names Acomplia, Zimulti) is an anorectic antiobesity drug that was first approved in Europe in 2006 but was withdrawn worldwide in 2008 due to serious psychiatric side effects; it was never approved in t ...
). A substantial number of antagonists of the CB1 receptor have been discovered and characterized.
TM38837
TM-38837 is a small molecule inverse agonist/ antagonist of the CB1 cannabinoid receptor, with peripheral selectivity. It is being developed for the treatment of obesity and metabolic disorders by 7TM Pharma. The company has announced phase I ...
has been developed as a CB1 receptor antagonist that is restricted to targeting only peripheral CB1 receptors.
Ligands
Agonists
*
Minocycline
Minocycline, sold under the brand name Minocin among others, is a tetracycline antibiotic medication used to treat a number of bacterial infections such as pneumonia. It is generally less preferred than the tetracycline doxycycline. It is also ...
*
Dronabinol
The International Nonproprietary Name Dronabinol, also known as delta-9-tetrahydrocannabinol, or under the trade names Marinol, Syndros, Reduvo and Adversa, is a generic name for the molecule of delta-9-tetrahydrocannabinol in the pharmaceutic ...
Selective
*
Epigallocatechin
Gallocatechol or gallocatechin (GC) is a flavan-3-ol, a type of chemical compound including catechin, with the gallate residue being in an isomeric trans position.
This compound possesses two epimers. The most common, (+)-gallocatechin (GC), CAS ...
*
Epicatechin
Catechin is a flavan-3-ol, a type of secondary metabolite providing antioxidant roles in plants. It belongs to the subgroup of polyphenols called flavonoids.
The name of the catechin chemical family derives from ''catechu'', which is the tanni ...
*
Kavain
Kavain is the main kavalactone found mostly in the roots of the kava plant.
Pharmacology
Kavain has anticonvulsive properties, attenuating vascular smooth muscle contraction through interactions with voltage-dependent and channels. How th ...
*
Yangonin
*
Oleamide
Oleamide is an organic compound with the formula CH3(CH2)7CH=CH(CH2)7CONH2(. It is the amide derived from the fatty acid oleic acid. It is a colorless waxy solid and occurs in nature. Sometimes labeled as a fatty acid primary amide (FAPA), it is ...
Unspecified efficacy
*
N-Arachidonoyl dopamine
''N''-Arachidonoyl dopamine (NADA) is an endocannabinoid that acts as an agonist of the CB1 receptor and the transient receptor potential V1 (TRPV1) ion channel. NADA was first described as a putative endocannabinoid (agonist for the CB1 recep ...
*
Cannabinol
Cannabinol (CBN) is a mildly psychoactive cannabinoid that acts as a low affinity partial agonist at both CB1 and CB2 receptors. This activity at CB1 and CB2 receptors constitutes interaction of CBN with the endocannabinoid system (ECS).
CBN ...
*
HU-210
HU-210 is a synthetic cannabinoid that was first synthesized in 1988 from (1R,5S)-myrtenol by a group led by Raphael Mechoulam at the Hebrew University. HU-210 is 100 to 800 times more potent than natural THC from cannabis and has an extended d ...
*
11-Hydroxy-THC
11-Hydroxy-Δ9-tetrahydrocannabinol (11-OH-Δ9-THC, alternatively numbered as 7-OH-Δ1-THC), usually referred to as 11-hydroxy-THC, is the main active metabolite of tetrahydrocannabinol (THC), which is formed in the body after THC is consumed.
...
*
Levonantradol
Partial
=Endogenous
=
*
2-Arachidonyl glyceryl ether
2-Arachidonyl glyceryl ether (2-AGE, Noladin ether) is a putative endocannabinoid discovered by Lumír Hanuš and colleagues at the Hebrew University of Jerusalem, Israel. It is an ether formed from the alcohol analog of arachidonic acid and g ...
=Phyto/synthetic
=
*
JWH-073
JWH-073, a synthetic cannabinoid, is an analgesic chemical from the naphthoylindole family that acts as a partial agonist at both the CB1 and CB2 cannabinoid receptors. It is somewhat selective for the CB1 subtype, with affinity at this subtype a ...
*
Tetrahydrocannabinol
Tetrahydrocannabinol (THC) is the principal psychoactive constituent of cannabis and one of at least 113 total cannabinoids identified on the plant. Although the chemical formula for THC (C21H30O2) describes multiple isomers, the term ''THC' ...
*
Hexahydrocannabinol
Full
=Endogenous
=
*
2-Arachidonoylglycerol
2-Arachidonoylglycerol (2-AG) is an endocannabinoid, an endogenous agonist of the CB1 receptor and the primary endogenous ligand for the CB2 receptor. It is an ester formed from the omega-6 fatty acid arachidonic acid and glycerol. It is present ...
=Phyto/synthetic
=
*
AM-2201
AM-2201 (1-(5-fluoropentyl)-3-(1-naphthoyl)indole) is a recreational designer drug that acts as a potent but nonselective full agonist for the cannabinoid receptor. It is part of the AM series of cannabinoids discovered by Alexandros Makriyanni ...
*
CP 55,940
55,940 is a synthetic cannabinoid which mimics the effects of naturally occurring THC (one of the psychoactive compounds found in cannabis). CP 55,940 was created by Pfizer in 1974 but was never marketed. It is currently used to study the endoca ...
*
JWH-018
JWH-018 (1-pentyl-3-(1-naphthoyl)indole, NA-PIMO or AM-678) is an analgesic chemical from the naphthoylindole family that acts as a full agonist at both the CB1 and CB2 cannabinoid receptors, with some selectivity for CB2. It produces effects in ...
*
WIN 55,212-2
WIN 55,212-2 is a chemical described as an aminoalkylindole derivative, which produces effects similar to those of cannabinoids such as tetrahydrocannabinol (THC) but has an entirely different chemical structure.
WIN 55,212-2 is a potent canna ...
Allosteric agonist
* GAT228
Antagonists
*
Cannabigerol
Cannabigerol (CBG) is one of more than 120 identified cannabinoid compounds found in the plant genus ''Cannabis''. Cannabigerol is the decarboxylated form of cannabigerolic acid, the parent molecule from which other cannabinoids are synthesized ...
*
Ibipinabant
*
Otenabant
*
Tetrahydrocannabivarin
Tetrahydrocannabivarin (THCV, THV, O-4394, GWP42004) is a homologue of tetrahydrocannabinol (THC) having a propyl (3-carbon) side chain instead of a pentyl (5-carbon) group on the molecule, which makes it produce very different effects from THC. ...
*
Virodhamine
Virodhamine (''O''-arachidonoyl ethanolamine; O-AEA) is an endocannabinoid and a nonclassic eicosanoid, derived from arachidonic acid. ''O''-Arachidonoyl ethanolamine is arachidonic acid and ethanolamine joined by an ester linkage, the opposite ...
(Endogenous CB1 antagonist and CB2 agonist)
Inverse agonists
*
Rimonabant
Rimonabant (also known as SR141716; trade names Acomplia, Zimulti) is an anorectic antiobesity drug that was first approved in Europe in 2006 but was withdrawn worldwide in 2008 due to serious psychiatric side effects; it was never approved in t ...
*
Taranabant
Taranabant (codenamed MK-0364) is a cannabinoid receptor type 1 (CB1) inverse agonist that was investigated as a potential treatment for obesity due to its anorectic effects. It was discovered by Merck & Co.
In October 2008, Merck has stopped ...
INV-202
Allosteric modulators
*
Lipoxin A4
A lipoxin (LX or Lx), an acronym for lipoxygenase interaction product, is a bioactive autacoid metabolite of arachidonic acid made by various cell types. They are categorized as nonclassic eicosanoids and members of the specialized pro-resolving ...
– endogenous, PAM
*
ZCZ-011
ZCZ-011 is a positive allosteric modulator of the cannabinoid
Cannabinoids () are several structural classes of compounds found in the cannabis plant primarily and most animal organisms (although insects lack such receptors) or as synthetic c ...
– PAM
*
Pregnenolone
Pregnenolone (P5), or pregn-5-en-3β-ol-20-one, is an endogenous steroid and precursor/ metabolic intermediate in the biosynthesis of most of the steroid hormones, including the progestogens, androgens, estrogens, glucocorticoids, and mineraloc ...
– endogenous, NAM
*
Cannabidiol
Cannabidiol (CBD) is a phytocannabinoid discovered in 1940. It is one of 113 identified cannabinoids in cannabis plants, along with tetrahydrocannabinol (THC), and accounts for up to 40% of the plant's extract. , clinical research on CBD in ...
– NAM
*
Fenofibrate
Fenofibrate (sold under the brand names ''Tricor'', ''Fenobrat'' etc.), is an oral medication of the fibrate class used to treat abnormal blood lipid levels. It is less commonly used compared than statins because it treats a different type of c ...
– NAM
*
GAT100
GAT100 is a negative allosteric modulator of the cannabinoid CB1 receptor.
See also
* Org 27569
* PSNCBAM-1
* ZCZ-011
ZCZ-011 is a positive allosteric modulator of the cannabinoid
Cannabinoids () are several structural classes of co ...
– NAM
*
PSNCBAM-1
PSNCBAM-1 is a negative allosteric modulator of the cannabinoid CB1 receptor.
See also
* GAT100
* Org 27569
* ZCZ-011
ZCZ-011 is a positive allosteric modulator of the cannabinoid
Cannabinoids () are several structural classes of compou ...
– NAM
*
RVD-Hpα – NAM
Binding affinities
Evolution
The CNR1 gene is used in animals as a
nuclear DNA
Nuclear DNA (nDNA), or nuclear deoxyribonucleic acid, is the DNA contained within each cell nucleus of a eukaryotic organism. It encodes for the majority of the genome in eukaryotes, with mitochondrial DNA and plastid DNA coding for the rest. I ...
phylogenetic marker.
This intronless gene has first been used to explore the phylogeny of the major groups of
mammals
Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur o ...
,
and contributed to reveal that
placental
Placental mammals (infraclass Placentalia ) are one of the three extant subdivisions of the class Mammalia, the other two being Monotremata and Marsupialia. Placentalia contains the vast majority of extant mammals, which are partly distinguishe ...
orders are distributed into five major clades:
Xenarthra
Xenarthra (; from Ancient Greek ξένος, xénos, "foreign, alien" + ἄρθρον, árthron, "joint") is a major clade of placental mammals native to the Americas. There are 31 living species: the anteaters, tree sloths, and armadillos. ...
,
Afrotheria
Afrotheria ( from Latin ''Afro-'' "of Africa" + ''theria'' "wild beast") is a clade of mammals, the living members of which belong to groups that are either currently living in Africa or of African origin: golden moles, elephant shrews (also k ...
,
Laurasiatheria
Laurasiatheria ("laurasian beasts") is a superorder of placental mammals that groups together true insectivores ( eulipotyphlans), bats ( chiropterans), carnivorans, pangolins ( pholidotes), even-toed ungulates ( artiodactyls), odd-toed ungulat ...
,
Euarchonta
The Euarchonta are a proposed grandorder of mammals: the order Scandentia (treeshrews), and its sister Primatomorpha mirorder, containing the Dermoptera or colugos and the primates (Plesiadapiformes and descendents).
The term "Euarchonta" (mea ...
, and
Glires
Glires (, Latin ''glīrēs'' 'dormice') is a clade (sometimes ranked as a grandorder) consisting of rodents and lagomorphs ( rabbits, hares, and pikas). The hypothesis that these form a monophyletic group has been long debated based on morp ...
. CNR1 has also proven useful at lower
taxonomic levels, such as
rodents,
and for the identification of
dermopterans as the closest primate relatives.
See also
*
Discovery and development of Cannabinoid Receptor 1 Antagonists
A cannabinoid receptor antagonist, also known simply as a cannabinoid antagonist or as an anticannabinoid, is a type of cannabinoidergic drug that binds to cannabinoid receptors (CBR) and prevents their activation by endocannabinoids. They include ...
*
Cannabinoid receptor
Cannabinoid receptors, located throughout the body, are part of the endocannabinoid system a class of cell membrane receptors in the G protein-coupled receptor superfamily. As is typical of G protein-coupled receptors, the cannabinoid recep ...
*
Cannabinoid receptor type 2
The cannabinoid receptor type 2, abbreviated as CB2, is a G protein-coupled receptor from the cannabinoid receptor family that in humans is encoded by the ''CNR2'' gene. It is closely related to the cannabinoid receptor type 1 (CB1), which is l ...
(CB
2)
References
External links
*
Cannabinoid receptor 1(CNR1) Human Protein Atlas
{{DEFAULTSORT:Cannabinoid Receptor Type 1
G protein-coupled receptors