JWH-133(Dimethylbutyl-deoxy-Delta-8-THC) is a potent selective CB2 receptor agonist with a Ki of 3.4nM and selectivity of around 200x for CB2 over CB1 receptors. It was discovered by and named after, John W. Huffman.
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. 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. The principal endogenous ligand for the CB2 receptor is 2-Arachidonoylglycerol (2-AG).
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.
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.
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.
SER-601 (COR-167) is a drug which acts as a potent and selective cannabinoid CB2 receptor agonist, based on a quinolone-3-carboxylic acid core structure, with 190 times selectivity for CB2 over the related CB1 receptor. It has analgesic effects in animal studies, as well as neuroprotective effects, but without a "cannabis high" due to its low affinity for CB1. A number of related compounds are known, almost all of which have high selectivity for CB2.
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.
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 26× 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 and 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.
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 17.4 nM vs 5,585 nM at CB1, giving it over 300× 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.
