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 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). The principal endogenous ligand for the CB2 receptor is 2-Arachidonoylglycerol (2-AG).
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, is a non-competitive CB1/CB2 receptor antagonist. And 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.
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.
A-834,735 is a drug developed by Abbott Laboratories that acts as a potent cannabinoid receptor full agonist at both the CB1 and CB2 receptors, with a Ki of 12 nM at CB1 and 0.21 nM at CB2. Replacing the aromatic 3-benzoyl or 3-naphthoyl group found in most indole derived cannabinoids, with the 3-tetramethylcyclopropylmethanone group of A-834,735 and related compounds, imparts significant selectivity for CB2, with most compounds from this group found to be highly selective CB2 agonists with little affinity for CB1. However low nanomolar CB1 binding affinity is retained with certain heterocyclic 1-position substituents such as (N-methylpiperidin-2-yl)methyl (cf. AM-1220, AM-1248), or the (tetrahydropyran-4-yl)methyl substituent of A-834,735, resulting in compounds that still show significant affinity and efficacy at both receptors despite being CB2 selective overall.
A-796,260 is a drug developed by Abbott Laboratories that acts as a potent and selective cannabinoid CB2 receptor agonist. Replacing the aromatic 3-benzoyl or 3-naphthoyl group found in most indole derived cannabinoids with the 3-tetramethylcyclopropylmethanone group, imparts significant selectivity for CB2, and A-796,260 was found to be a highly selective CB2 agonist with little affinity for CB1, having a CB2Ki of 4.6 nM vs 945 nM at CB1. It has potent analgesic and anti-inflammatory actions in animal models, being especially effective in models of neuropathic pain, but without producing cannabis-like behavioral effects.
AM-630 (6-Iodopravadoline) is a drug that acts as a potent and selective inverse agonist for the cannabinoid receptor CB2, with a Ki of 32.1 nM at CB2 and 165x selectivity over CB1, at which it acted as a weak partial agonist. It is used in the study of CB2 mediated responses and has been used to investigate the possible role of CB2 receptors in the brain. AM-630 is significant as one of the first indole derived cannabinoid ligands substituted on the 6-position of the indole ring, a position that has subsequently been found to be important in determining affinity and efficacy at both the CB1 and CB2 receptors, and has led to the development of many related derivatives.
AM-2233 is a drug that acts as a highly potent full agonist for the cannabinoid receptors, with a Ki of 1.8 nM at CB1 and 2.2 nM at CB2 as the active (R) enantiomer. It was developed as a selective radioligand for the cannabinoid receptors and has been used as its 131I derivative for mapping the distribution of the CB1 receptor in the brain. AM-2233 was found to fully substitute for THC in rats, with a potency lower than that of JWH-018 but higher than WIN 55,212-2.
AZ-11713908 is a drug developed by AstraZeneca which is a peripherally selective cannabinoid agonist, acting as a potent agonist at the CB1 receptor and a partial agonist at CB2. It has poor blood–brain barrier penetration, and so while it is an effective analgesic in animal tests, it produces only peripheral effects at low doses, with much weaker symptoms of central effects compared to other cannabinoid drugs such as WIN 55,212-2. Many related benzimidazole-derived cannabinoid ligands are known.
O-1269 is a drug that is a diarylpyrazole derivative, related to potent cannabinoid antagonist drugs such as rimonabant and surinabant. However O-1269 and several related drugs were unexpectedly found to act as full or partial agonists at the cannabinoid receptors rather than antagonists, and so produce the usual effects expected of cannabinoid agonists in animal tests, such as sedation and analgesic effects. The N-heptyl homolog O-1270 and the N-propyl homolog O-1399 also act as cannabinoid agonists with similar potency in vivo, despite weaker binding affinity at cannabinoid receptors compared to the pentyl homolog O-1269. Agonist-like and atypical cannabinoid activity has also been observed with a number of related compounds.
AM-2389 is a classical cannabinoid derivative which acts as a potent and reasonably selective agonist for the CB1 receptor, with a Ki of 0.16 nM, and 26x selectivity over the related CB2 receptor. It has high potency in animal tests of cannabinoid activity, and a medium duration of action. Replacing the 1',1'-dimethyl substitution of the dimethylheptyl side chain of classical cannabinoids with cyclopropyl or cyclopentyl results in higher potency than cyclobutyl, but only the cyclobutyl derivatives show selectivity for CB1 over CB2. High selectivity for CB1 over CB2 is difficult to achieve (cf. AM-906, AM-1235), as almost all commonly used CB1 agonists have similar or greater affinity for CB2 than CB1, and the only truly highly selective CB1 agonists known as of 2012 are eicosanoid derivatives such as O-1812.
CBS-0550 is a drug developed by Taisho Pharmaceutical, which acts as a potent and selective cannabinoid CB2 receptor agonist, with 1400x selectivity for CB2 over the related CB1 receptor. Unlike most cannabinoid agonists, CBS-0550 has good solubility in water, and in animal studies it was found to produce analgesic and anti-hyperalgesic effects. A number of related compounds have been developed with similar properties.
LBP-1 is a drug originally developed by Organon for the treatment of neuropathic pain, It acts as a potent and selective cannabinoid receptor agonist, with high potency at both the CB1 and CB2 receptors, but low penetration of the blood–brain barrier. This makes LBP-1 peripherally selective, and while it was effective in animal models of neuropathic pain and allodynia, it did not produce cannabinoid-appropriate responding suggestive of central effects, at any dose tested.
S-444,823 is a drug developed by Shionogi which is a cannabinoid agonist. It was developed as an antipruritic, and has moderate selectivity for the CB2 subtype, having a CB2 affinity of 18nM, and 32x selectivity over the CB1 receptor. In animal studies it showed analgesic effects and strongly reduced itching responses, but without producing side effects such as sedation and catalepsy that are seen with centrally acting CB1 agonists.
PF-03550096 is a drug that acts as a potent agonist for the CB2 cannabinoid receptor, with good selectivity over CB1 having Ki values of 7nM at CB2 and 1500nM at CB1. It was originally developed by Pfizer in 2008 as a medication for irritable bowel syndrome, but has only progressed to animal studies.
Olorinab (APD371) is a drug being developed by Arena Pharmaceuticals for the treatment of gastrointestinal pain associated with Crohn's disease and irritable bowel syndrome. It acts as a potent and selective cannabinoid CB2 receptor agonist and is claimed to be orally active and peripherally selective. Initial Phase IIa exploratory clinical trials have been successful in patients with quiescent Crohn's disease. Arena initiated the Phase IIb Captivate trial in late July 2019 in patients with irritable bowel syndrome related pain, in constipation and diarrhea predominant sub-types. The Phase IIb trial is expected to enroll 240 participants between the ages of 18 to 70.Three doses of 10 mg, 25 mg, and 50 mg are being tested against Placebo in a 3:4 prescription ratio with a Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) masking layout.
AZD-1940 is a drug developed by AstraZeneca, that is a peripherally selective cannabinoid agonist which binds with high affinity to both the CB1 and CB2 receptors. It was developed for the treatment of neuropathic pain, but while it showed good peripheral selectivity in animal studies, in human clinical trials it failed to show sufficient analgesic efficacy and produced unexpectedly strong side effects associated with central cannabinoid activity, and so was discontinued from further development.
Cannabinor (PRS-211,375) is a drug which acts as a potent and selective cannabinoid CB2 receptor agonist. It is classed as a "nonclassical" cannabinoid with a chemical structure similar to that of cannabidiol. It has a CB2 affinity of 17.4nM vs 5585nM at CB1, giving it over 300x selectivity for CB2. It showed analgesic effects in animal studies especially in models of neuropathic pain, but failed in Phase IIb human clinical trials due to lack of efficacy.
S-777,469 is a drug developed by Shionogi which is a cannabinoid receptor agonist, with 128x selectivity for the CB2 subtype, having a CB2 affinity of 36nM, and a CB1 affinity over 4600nM. In animal studies it showed antipruritic effects, and passed Phase II human trials for the treatment of atopic dermatitis, but development was ultimately not continued further.
