Cannabinoid receptor 2

Last updated
CNR2
Human cannabinoid receptor 2 (CB2) PDB 5ZTY.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases CNR2 , CB-2, CB2, CX5, Cannabinoid receptor type 2, cannabinoid receptor 2
External IDs OMIM: 605051 MGI: 104650 HomoloGene: 1389 GeneCards: CNR2
Orthologs
SpeciesHumanMouse
Entrez

1269

12802

Ensembl

ENSG00000188822

ENSMUSG00000062585

UniProt

P34972

P47936

RefSeq (mRNA)

NM_001841

NM_009924
NM_001305278

RefSeq (protein)

NP_001832

NP_001292207
NP_034054

Location (UCSC) Chr 1: 23.87 – 23.91 Mb Chr 4: 135.62 – 135.65 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

The cannabinoid receptor 2(CB2), is a G protein-coupled receptor from the cannabinoid receptor family that in humans is encoded by the CNR2 gene. [5] [6] It is closely related to the cannabinoid receptor 1 (CB1), which is largely responsible for the efficacy of endocannabinoid-mediated presynaptic-inhibition, the psychoactive properties of tetrahydrocannabinol (THC), the active agent in cannabis, and other phytocannabinoids (plant cannabinoids). [5] [7] The principal endogenous ligand for the CB2 receptor is 2-Arachidonoylglycerol (2-AG). [6]

Contents

CB2 was cloned in 1993 by a research group from Cambridge looking for a second cannabinoid receptor that could explain the pharmacological properties of tetrahydrocannabinol. [5] The receptor was identified among cDNAs based on its similarity in amino-acid sequence to the cannabinoid receptor 1 (CB1) receptor, discovered in 1990. [8] The discovery of this receptor helped provide a molecular explanation for the established effects of cannabinoids on the immune system.

Structure

The CB2 receptor is encoded by the CNR2 gene. [5] [9] Approximately 360 amino acids comprise the human CB2 receptor, making it somewhat shorter than the 473-amino-acid-long CB1 receptor. [9]

As is commonly seen in G protein-coupled receptors, the CB2 receptor has seven transmembrane spanning domains, [10] a glycosylated N-terminus, and an intracellular C-terminus. [9] The C-terminus of CB2 receptors appears to play a critical role in the regulation of ligand-induced receptor desensitization and downregulation following repeated agonist application, [9] perhaps causing the receptor to become less responsive to particular ligands.

The human CB1 and the CB2 receptors possess approximately 44% amino acid similarity. [5] When only the transmembrane regions of the receptors are considered, however, the amino acid similarity between the two receptor subtypes is approximately 68%. [9] The amino acid sequence of the CB2 receptor is less highly conserved across human and rodent species as compared to the amino acid sequence of the CB1 receptor. [11] Based on computer modeling, ligand interactions with CB2 receptor residues S3.31 and F5.46 appears to determine differences between CB1 and CB2 receptor selectivity. [12] In CB2 receptors, lipophilic groups interact with the F5.46 residue, allowing them to form a hydrogen bond with the S3.31 residue. [12] These interactions induce a conformational change in the receptor structure, which triggers the activation of various intracellular signaling pathways. Further research is needed to determine the exact molecular mechanisms of signaling pathway activation. [12]

Mechanism

Like the CB1 receptors, CB2 receptors inhibit the activity of adenylyl cyclase through their Gi/Goα subunits. [13] [14] CB2 can also couple to stimulatory Gαs subunits leading to an increase of intracellular cAMP, as has been shown for human leukocytes. [15] Through their Gβγ subunits, CB2 receptors are also known to be coupled to the MAPK-ERK pathway, [13] [14] [16] a complex and highly conserved signal transduction pathway, which regulates a number of cellular processes in mature and developing tissues. [17] Activation of the MAPK-ERK pathway by CB2 receptor agonists acting through the Gβγ subunit ultimately results in changes in cell migration. [18]

Five recognized cannabinoids are produced endogenously: arachidonoylethanolamine (anandamide), 2-arachidonoyl glycerol (2-AG), 2-arachidonyl glyceryl ether (noladin ether), virodhamine, [13] as well as N-arachidonoyl-dopamine (NADA). [19] Many of these ligands appear to exhibit properties of functional selectivity at the CB2 receptor: 2-AG activates the MAPK-ERK pathway, while noladin inhibits adenylyl cyclase. [13]

Expression

Dispute

Originally it was thought that the CB2 receptor was only expressed in peripheral tissue while the CB1 receptor is the endogenous receptor on neurons. Recent work with immunohistochemical staining has shown expression within neurons. Subsequently, it was shown that CB2 knock out mice produced the same immunohistochemical staining, indicating the presence of the CB2 receptor where none was expressed. This has created a long history of debate as to whether the CB2 receptor is expressed in the CNS. A new mouse model was described in 2014 that expresses a fluorescent protein whenever CB2 is expressed within a cell. This has the potential to resolve questions about the expression of CB2 receptors in various tissues. [20]

Immune system

Initial investigation of CB2 receptor expression patterns focused on the presence of CB2 receptors in the peripheral tissues of the immune system, [10] and found the CB2 receptor mRNA in the spleen, tonsils, and thymus gland. [10] CB2 expression in human peripheral blood mononuclear cells at protein level has been confirmed by whole cell radioligand binding. [15] Northern blot analysis further indicates the expression of the CNR2 gene in immune tissues, [10] where they are primarily responsible for mediating cytokine release. [21] These receptors were localized on immune cells such as monocytes, macrophages, B-cells, and T-cells. [6] [10]

Brain

Further investigation into the expression patterns of the CB2 receptors revealed that CB2 receptor gene transcripts are also expressed in the brain, though not as densely as the CB1 receptor and located on different cells. [22] Unlike the CB1 receptor, in the brain, CB2 receptors are found primarily on microglia. [21] [23] The CB2 receptor is expressed in some neurons within the central nervous system (e.g.; the brainstem), but the expression is very low. [24] [25] CB2s are expressed on some rat retinal cell types. [26] Functional CB2 receptors are expressed in neurons of the ventral tegmental area and the hippocampus, arguing for a widespread expression and functional relevance in the CNS and in particular in neuronal signal transmission. [27] [28]

Gastrointestinal system

CB2 receptors are also found throughout the gastrointestinal system, where they modulate intestinal inflammatory response. [29] [30] Thus, CB2 receptor is a potential therapeutic target for inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis. [30] [31] The role of endocannabinoids, as such, play an important role in inhibiting unnecessary immune action upon the natural gut flora. Dysfunction of this system, perhaps from excess FAAH activity, could result in IBD. CB2 activation may also have a role in the treatment of irritable bowel syndrome. [32] Cannabinoid receptor agonists reduce gut motility in IBS patients. [33]

Peripheral nervous system

Application of CB2-specific antagonists has found that these receptors are also involved in mediating analgesic effects in the peripheral nervous system. However, these receptors are not expressed by nociceptive sensory neurons, and at present are believed to exist on an undetermined, non-neuronal cell. Possible candidates include mast cells, known to facilitate the inflammatory response. Cannabinoid mediated inhibition of these responses may cause a decrease in the perception of noxious-stimuli. [8]

Function

Immune system

Primary research on the functioning of the CB2 receptor has focused on the receptor's effects on the immunological activity of leukocytes. [34] To be specific, this receptor has been implicated in a variety of modulatory functions, including immune suppression, induction of apoptosis, and induction of cell migration. [6] 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). [35] [36] CB2 also signals via Gαs and increases intracellular cAMP in human leukocytes, leading to induction of interleukins 6 and 10. [15] 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 binding of transcription factor CREB (cAMP response element-binding protein) to DNA. [34] This reduction causes changes in the expression of critical immunoregulatory genes [35] and ultimately suppression of immune function. [36]

Later studies examining the effect of synthetic cannabinoid agonist JWH-015 on CB2 receptors revealed that changes in cAMP levels result in the phosphorylation of leukocyte receptor tyrosine kinase at Tyr-505, leading to an inhibition of T cell receptor signaling. Thus, CB2 agonists may also be useful for treatment of inflammation and pain, and are currently being investigated, in particular for forms of pain that do not respond well to conventional treatments, such as neuropathic pain. [37] Consistent with these findings are studies that demonstrate increased CB2 receptor expression in the spinal cord, dorsal root ganglion, and activated microglia in the rodent neuropathic pain model, as well as on human hepatocellular carcinoma tumor samples. [38]

CB2 receptors have also been implicated in the regulation of homing and retention of marginal zone B cells. A study using knock-out mice found that CB2 receptor is essential for the maintenance of both MZ B cells and their precursor T2-MZP, though not their development. Both B cells and their precursors lacking this receptor were found in reduced numbers, explained by the secondary finding that 2-AG signaling was demonstrated to induce proper B cell migration to the MZ. Without the receptor, there was an undesirable spike in the blood concentration of MZ B lineage cells and a significant reduction in the production of IgM. While the mechanism behind this process is not fully understood, the researchers suggested that this process may be due to the activation-dependent decrease in cAMP concentration, leading to reduced transcription of genes regulated by CREB, indirectly increasing TCR signaling and IL-2 production. [6] Together, these findings demonstrate that the endocannabinoid system may be exploited to enhance immunity to certain pathogens and autoimmune diseases.

Clinical applications

CB2 receptors may have possible therapeutic roles in the treatment of neurodegenerative disorders such as Alzheimer's disease. [39] [40] Specifically, the CB2 agonist JWH-015 was shown to induce macrophages to remove native beta-amyloid protein from frozen human tissues. [41] In patients with Alzheimer's disease, beta-amyloid proteins form aggregates known as senile plaques, which disrupt neural functioning. [42]

Changes in endocannabinoid levels and/or CB2 receptor expressions have been reported in almost all diseases affecting humans, [43] ranging from cardiovascular, gastrointestinal, liver, kidney, neurodegenerative, psychiatric, bone, skin, autoimmune, lung disorders to pain and cancer. The prevalence of this trend suggests that modulating CB2 receptor activity by either selective CB2 receptor agonists or inverse agonists/antagonists depending on the disease and its progression holds unique therapeutic potential for these pathologies [43]

Modulation of cocaine reward

Researchers investigated the effects of CB2 agonists on cocaine self-administration in mice. Systemic administration of JWH-133 reduced the number of self-infusions of cocaine in mice, as well as reducing locomotor activity and the break point (maximum amount of level presses to obtain cocaine). Local injection of JWH-133 into the nucleus accumbens was found to produce the same effects as systemic administration. Systemic administration of JWH-133 also reduced basal and cocaine-induced elevations of extracellular dopamine in the nucleus accumbens. These findings were mimicked by another, structurally different CB2 agonist, GW-405,833, and were reversed by the administration of a CB2 antagonist, AM-630. [44]

Ligands

Many selective ligands for the CB2 receptor are now available. [45]

Agonists

Partial agonists

Unspecified efficacy agonists

Herbal

Inverse agonists

Binding affinities

CB1 affinity (Ki)Efficacy towards CB1CB2 affinity (Ki)Efficacy towards CB2TypeReferences
Anandamide 78 nMPartial agonist370 nMPartial agonistEndogenous
N-Arachidonoyl dopamine 250 nMAgonist12000 nM ?Endogenous [48]
2-Arachidonoylglycerol 58.3 nMFull agonist145 nMFull agonistEndogenous [48]
2-Arachidonyl glyceryl ether 21 nMFull agonist480 nMFull agonistEndogenous
Tetrahydrocannabinol 10 nMPartial agonist24 nMPartial agonistPhytogenic [49]
EGCG 33.6 μMAgonist>50 μM ?Phytogenic [50]
EGC 35.7 μMAgonist>50 μM?Phytogenic [50]
ECG 47.3 μMAgonist>50 μM?Phytogenic [50]
N-alkylamide--<100 nMPartial agonistPhytogenic [51]
β- Caryophyllene --<200 nMFull agonistPhytogenic [51]
Falcarinol <1 μMInverse agonist??Phytogenic [51]
Rutamarin --<10 μM?Phytogenic [51]
3,3'-Diindolylmethane --1 μMPartial AgonistPhytogenic [51]
AM-1221 52.3 nMAgonist0.28 nMAgonistSynthetic [52]
AM-1235 1.5 nMAgonist20.4 nMAgonistSynthetic [53]
AM-2232 0.28 nMAgonist1.48 nMAgonistSynthetic [53]
UR-144 150 nMFull agonist1.8 nMFull agonistSynthetic [54]
JWH-007 9.0 nMAgonist2.94 nMAgonistSynthetic [55]
JWH-015 383 nMAgonist13.8 nMAgonistSynthetic [55]
JWH-018 9.00 ± 5.00 nMFull agonist2.94 ± 2.65 nMFull agonistSynthetic [55]

Evolution

Paralogues [56]

Related Research Articles

<span class="mw-page-title-main">Anandamide</span> Chemical compound (fatty acid neurotransmitter)

Anandamide (ANA), also known as N-arachidonoylethanolamine (AEA), an N-acylethanolamine (NAE), 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 receptors, the same receptors that the psychoactive compound THC in cannabis acts on. Anandamide is found in nearly all tissues in a wide range of animals. Anandamide has also been found in plants, including small amounts in chocolate. The name 'anandamide' is taken from the Sanskrit word ananda, which means "joy, bliss, delight", plus amide.

<span class="mw-page-title-main">Cannabinoid</span> Compounds found in cannabis

Cannabinoids are several structural classes of compounds found in the cannabis plant primarily and most animal organisms or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoactive compound in cannabis. Cannabidiol (CBD) is also a major constituent of temperate cannabis plants and a minor constituent in tropical varieties. At least 113 distinct phytocannabinoids have been isolated from cannabis, although only four have been demonstrated to have a biogenetic origin. It was reported in 2020 that phytocannabinoids can be found in other plants such as rhododendron, licorice and liverwort, and earlier in Echinacea.

<span class="mw-page-title-main">Cannabinoid receptor</span> Group of receptors to cannabinoid compounds

Cannabinoid receptors, located throughout the body, are part of the endocannabinoid system of vertebrates– a class of cell membrane receptors in the G protein-coupled receptor superfamily. As is typical of G protein-coupled receptors, the cannabinoid receptors contain seven transmembrane spanning domains. Cannabinoid receptors are activated by three major groups of ligands: endocannabinoids; phytocannabinoids ; and synthetic cannabinoids. All endocannabinoids and phytocannabinoids are lipophilic.

<span class="mw-page-title-main">Cannabinol</span> Naturally-occurring cannabinoid

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).

The endocannabinoid system (ECS) is a biological system composed of endocannabinoids, which are endogenous lipid-based retrograde neurotransmitters that bind to cannabinoid receptors (CBRs), and cannabinoid receptor proteins that are expressed throughout the vertebrate central nervous system and peripheral nervous system. The endocannabinoid system remains under preliminary research, but may be involved in regulating physiological and cognitive processes, including fertility, pregnancy, pre- and postnatal development, various activity of immune system, appetite, pain-sensation, mood, and memory, and in mediating the pharmacological effects of cannabis. The ECS plays an important role in multiple aspects of neural functions, including the control of movement and motor coordination, learning and memory, emotion and motivation, addictive-like behavior and pain modulation, among others.

<span class="mw-page-title-main">2-Arachidonoylglycerol</span> Chemical compound

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 at relatively high levels in the central nervous system, with cannabinoid neuromodulatory effects. It has been found in maternal bovine and human milk. The chemical was first described in 1994–1995, although it had been discovered some time before that. The activities of phospholipase C (PLC) and diacylglycerol lipase (DAGL) mediate its formation. 2-AG is synthesized from arachidonic acid-containing diacylglycerol (DAG).

<span class="mw-page-title-main">Cannabinoid receptor 1</span> Mammalian protein found in Homo sapiens

Cannabinoid receptor 1 (CB1), is a G protein-coupled cannabinoid receptor that in humans is encoded by the CNR1 gene. The human CB1 receptor is expressed in the peripheral nervous system and central nervous system. It is activated by endocannabinoids, a group of retrograde neurotransmitters that include anandamide and 2-arachidonoylglycerol (2-AG); plant phytocannabinoids, such as docosatetraenoylethanolamide found in wild daga, the compound THC which is an active constituent of the psychoactive drug cannabis; and synthetic analogs of THC. CB1 is antagonized by the phytocannabinoid tetrahydrocannabivarin (THCV).

<i>N</i>-Arachidonoyl dopamine Chemical compound

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 receptor) in 2000 and was subsequently identified as an endovanilloid (agonist for TRPV1) in 2002. NADA is an endogenous arachidonic acid based lipid found in the brain of rats, with especially high concentrations in the hippocampus, cerebellum, and striatum. It activates the TRPV1 channel with an EC50 of approximately of 50 nM which makes it the putative endogenous TRPV1 agonist.

<span class="mw-page-title-main">JWH-018</span> Chemical compound

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 animals similar to those of tetrahydrocannabinol (THC), a cannabinoid naturally present in cannabis, leading to its use in synthetic cannabis products that in some countries are sold legally as "incense blends".

<span class="mw-page-title-main">JWH-073</span> Chemical compound

JWH-073, a synthetic cannabinoid, is an analgesic chemical from the naphthoylindole family that acts as a full agonist at both the CB1 and CB2 cannabinoid receptors. It is somewhat selective for the CB1 subtype, with affinity at this subtype approximately 5× the affinity at CB2. The abbreviation JWH stands for John W. Huffman, one of the inventors of the compound.

<span class="mw-page-title-main">JWH-015</span> Chemical compound

JWH-015 is a chemical from the naphthoylindole family that acts as a subtype-selective cannabinoid agonist. Its affinity for CB2 receptors is 13.8 nM, while its affinity for CB1 is 383 nM, meaning that it binds almost 28 times more strongly to CB2 than to CB1. However, it still displays some CB1 activity, and in some model systems can be very potent and efficacious at activating CB1 receptors, and therefore it is not as selective as newer drugs such as JWH-133. It has been shown to possess immunomodulatory effects, and CB2 agonists may be useful in the treatment of pain and inflammation. It was discovered and named after John W. Huffman.

<span class="mw-page-title-main">BML-190</span> Chemical compound

BML-190 (Indomethacin morpholinylamide) is a drug used in scientific research that acts as a selective CB2 inverse agonist. BML-190 is structurally derived from the NSAID indomethacin but has a quite different biological activity. The activity produced by this compound is disputed, with some sources referring to it as a CB2 agonist rather than an inverse agonist; this may reflect an error in classification, or alternatively it may produce different effects in different tissues, and more research is required to resolve this dispute.

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 antagonists, inverse agonists, and antibodies of CBRs. The discovery of the endocannabinoid system led to the development of CB1 receptor antagonists. The first CBR inverse agonist, rimonabant, was described in 1994. Rimonabant blocks the CB1 receptor selectively and has been shown to decrease food intake and regulate body-weight gain. The prevalence of obesity worldwide is increasing dramatically and has a great impact on public health. The lack of efficient and well-tolerated drugs to cure obesity has led to an increased interest in research and development of CBR antagonists. Cannabidiol (CBD), a naturally occurring cannabinoid and a non-competitive CB1/CB2 receptor antagonist, as well as Δ9-tetrahydrocannabivarin (THCV), a naturally occurring cannabinoid, modulate the effects of THC via direct blockade of cannabinoid CB1 receptors, thus behaving like first-generation CB1 receptor inverse agonists, such as rimonabant. CBD is a very low-affinity CB1 ligand, that can nevertheless affect CB1 receptor activity in vivo in an indirect manner, while THCV is a high-affinity CB1 receptor ligand and potent antagonist in vitro and yet only occasionally produces effects in vivo resulting from CB1 receptor antagonism. THCV has also high affinity for CB2 receptors and signals as a partial agonist, differing from both CBD and rimonabant.

<i>N</i>-Acylethanolamine Class of chemical compounds

An N-acylethanolamine (NAE) is a type of fatty acid amide where one of several types of acyl groups is linked to the nitrogen atom of ethanolamine, and highly metabolic formed by intake of essential fatty acids through diet by 20:4, n-6 and 22:6, n-3 fatty acids, and when the body is physically and psychologically active,. The endocannabinoid signaling system (ECS) is the major pathway by which NAEs exerts its physiological effects in animal cells with similarities in plants, and the metabolism of NAEs is an integral part of the ECS, a very ancient signaling system, being clearly present from the divergence of the protostomian/deuterostomian, and even further back in time, to the very beginning of bacteria, the oldest organisms on Earth known to express phosphatidylethanolamine, the precursor to endocannabinoids, in their cytoplasmic membranes. Fatty acid metabolites with affinity for CB receptors are produced by cyanobacteria, which diverged from eukaryotes at least 2000 million years ago (MYA), by brown algae which diverged about 1500 MYA, by sponges, which diverged from eumetazoans about 930 MYA, and a lineages that predate the evolution of CB receptors, as CB1 – CB2 duplication event may have occurred prior to the lophotrochozoan-deuterostome divergence 590 MYA. Fatty acid amide hydrolase (FAAH) evolved relatively recently, either after the evolution of fish 400 MYA, or after the appearance of mammals 300 MYA, but after the appearance of vertebrates. Linking FAAH, vanilloid receptors (VR1) and anandamide implies a coupling among the remaining ‘‘older’’ parts of the endocannabinoid system, monoglyceride lipase (MGL), CB receptors, that evolved prior to the metazoan-bilaterian divergence, but were secondarily lost in the Ecdysozoa, and 2-Arachidonoylglycerol (2-AG).

<span class="mw-page-title-main">AM-1241</span> Chemical compound

AM-1241 (1-(methylpiperidin-2-ylmethyl)-3-(2-iodo-5-nitrobenzoyl)indole) is a chemical from the aminoalkylindole family that acts as a potent and selective agonist for the cannabinoid receptor CB2, with a Ki of 3.4 nM at CB2 and 80 times selectivity over the related CB1 receptor. It has analgesic effects in animal studies, particularly against "atypical" pain such as hyperalgesia and allodynia. This is thought to be mediated through CB2-mediated peripheral release of endogenous opioid peptides, as well as direct activation of the TRPA1 channel. It has also shown efficacy in the treatment of amyotrophic lateral sclerosis in animal models.

<span class="mw-page-title-main">Abnormal cannabidiol</span> Synthetic, cannabinoid-like compound

Abnormal cannabidiol (Abn-CBD) is a synthetic regioisomer of cannabidiol, which unlike most other cannabinoids produces vasodilator effects, lowers blood pressure, and induces cell migration, cell proliferation and mitogen-activated protein kinase activation in microglia, but without producing any psychoactive effects.

RVD-Hpα (pepcan-12) is an endogenous neuropeptide found in human and mammalian brain, which was originally proposed to act as a selective agonist for the CB1 cannabinoid receptor. It is a 12-amino acid polypeptide having the amino acid sequence Arg-Val-Asp-Pro-Val-Asn-Phe-Lys-Leu-Leu-Ser-His and is an N-terminal extended form of hemopressin, a 9-AA polypeptide derived from the α1 subunit of hemoglobin which has previously been shown to act as a CB1 inverse agonist. All three polypeptides have been isolated from various mammalian species, with RVD-Hpα being one of the more abundant neuropeptides expressed in mouse brain, and these neuropeptides represent a new avenue for cannabinoid research distinct from the previously known endogenous lipid-derived cannabinoid agonists such as anandamide. Recently it was shown that RVD-Hpα (also called Pepcan-12) is a potent negative allosteric modulator at CB1 receptors, together with other newly described N-terminally extended peptides (pepcans).

<span class="mw-page-title-main">JWH-019</span> Chemical compound

JWH-019 is an analgesic chemical from the naphthoylindole family that acts as a cannabinoid agonist at both the CB1 and CB2 receptors. It is the N-hexyl homolog of the more common synthetic cannabinoid compound JWH-018. Unlike the butyl homolog JWH-073, which is several times weaker than JWH-018, the hexyl homolog is only slightly less potent, although extending the chain one carbon longer to the heptyl homolog JWH-020 results in dramatic loss of activity. These results show that the optimum side chain length for CB1 binding in the naphthoylindole series is the five-carbon pentyl chain, shorter than in the classical cannabinoids where a seven-carbon heptyl chain produces the most potent compounds. This difference is thought to reflect a slightly different binding conformation adopted by the naphthoylindole compounds as compared to the classical cannabinoids, and may be useful in characterizing the active site of the CB1 and CB2 receptors.

<span class="mw-page-title-main">SR-144,528</span> Chemical compound

SR144528 is a drug that acts as a potent and highly selective CB2 receptor inverse agonist, with a Ki of 0.6 nM at CB2 and 400 nM at the related CB1 receptor. It is used in scientific research for investigating the function of the CB2 receptor, as well as for studying the effects of CB1 receptors in isolation, as few CB1 agonists that do not also show significant activity as CB2 agonists are available. It has also been found to be an inhibitor of sterol O-acyltransferase, an effect that appears to be independent from its action on CB2 receptors.

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