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 Dr. John W. Huffman.
AM-694 (1-(5-fluoropentyl)-3-(2-iodobenzoyl)indole) is a designer drug that acts as a potent and selective agonist for the cannabinoid receptor CB1. It is used in scientific research for mapping the distribution of CB1 receptors.
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.
JWH-007 is an analgesic chemical from the naphthoylindole family, which acts as a cannabinoid agonist at both the CB1 and CB2 receptors. It was the most active of the first group of N-alkyl naphoylindoles discovered by the team led by John W Huffman, several years after the family was initially described with the discovery of the N-morpholinylethyl compounds pravadoline (WIN 48,098), JWH-200 (WIN 55,225) and WIN 55,212-2 by the Sterling Winthrop group. Several other N-alkyl substituents were found to be active by Huffman's team including the n-butyl, n-hexyl, 2-heptyl, and cyclohexylethyl groups, but it was subsequently determined that the 2-methyl group on the indole ring is not required for CB1 binding, and tends to increase affinity for CB2 instead. Consequently, the 2-desmethyl derivative of JWH-007, JWH-018, has slightly higher binding affinity for CB1, with an optimum binding of 9.00 nM at CB1 and 2.94 nM at CB2, and JWH-007 displayed optimum binding of 9.50 nM at CB1 and 2.94 nM at CB2.
HU-243 (AM-4056) is a synthetic cannabinoid drug that is a single enantiomer of the hydrogenated derivative of the commonly used reference agonist HU-210. It is a methylene homologue of canbisol. It is a potent agonist at both the CB1 and CB2 receptors, with a binding affinity of 0.041 nM at the CB1 receptor, making it marginally more potent than HU-210, which had an affinity of 0.061 nM in the same assay.
AM-2201 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 Makriyannis at Northeastern University.
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-1221 is a drug that acts as a potent and selective agonist for the cannabinoid receptor CB2, with a Ki of 0.28 nM at CB2 and 52.3 nM at the CB1 receptor, giving it around 180 times selectivity for CB2. The 2-methyl and 6-nitro groups on the indole ring both tend to increase CB2 affinity while generally reducing affinity at CB1, explaining the high CB2 selectivity of AM-1221. However, despite this relatively high selectivity for CB2, its CB1 affinity is still too strong to make it useful as a truly selective CB2 agonist, so the related compound AM-1241 is generally preferred for research purposes.
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-679 (part of the AM cannabinoid series) is a drug that acts as a moderately potent agonist for the cannabinoid receptors, with a Ki of 13.5 nM at CB1 and 49.5 nM at CB2. AM-679 was one of the first 3-(2-iodobenzoyl)indole derivatives that was found to have significant cannabinoid receptor affinity, and while AM-679 itself has only modest affinity for these receptors, it was subsequently used as a base to develop several more specialised cannabinoid ligands that are now widely used in research, including the potent CB1 agonists AM-694 and AM-2233, and the selective CB2 agonist AM-1241. AM-679 was first identified as having been sold as a cannabinoid designer drug in Hungary in 2011, along with another novel compound 1-pentyl-3-(1-adamantoyl)indole.
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.
AM-1248 is a drug that acts as a moderately potent agonist for both the cannabinoid receptors CB1 and CB2, but with some dispute between sources over its exact potency and selectivity. Replacing the 3-(1-naphthoyl) group found in many indole derived cannabinoid ligands, with an adamantoyl group, generally confers significant CB2 selectivity, but reasonable CB1 affinity and selectivity is retained when an N-methylpiperidin-2-ylmethyl substitution is used at the indole 1-position. The related compound 1-pentyl-3-(1-adamantoyl)indole was identified as having been sold as a cannabinoid designer drug in Hungary in 2011, along with another synthetic cannabinoid AM-679.
AM-2232 (1-(4-cyanobutyl)-3-(naphthalen-1-oyl)indole) is a drug that acts as a potent but unselective agonist for the cannabinoid receptors, with a Ki of 0.28 nM at CB1 and 1.48 nM at CB2.
AM-1235 (1-(5-fluoropentyl)-3-(naphthalen-1-oyl)-6-nitroindole) is a drug that acts as a potent and reasonably selective agonist for the cannabinoid receptor CB1.
JWH-198 is a drug from the aminoalkylindole and naphthoylindole families which acts as a cannabinoid receptor agonist. It was invented by the pharmaceutical company Sanofi-Winthrop in the early 1990s. JWH-198 has a binding affinity at the CB1 receptor of 10 nM, binding around four times more tightly than the parent compound JWH-200, which has no substitution on the naphthoyl ring. It has been used mainly in molecular modelling of the cannabinoid receptors.
JWH-193 is a drug from the aminoalkylindole and naphthoylindole families which acts as a cannabinoid receptor agonist. It was invented by the pharmaceutical company Sanofi-Winthrop in the early 1990s. JWH-193 has a binding affinity at the CB1 receptor of 6 nM, binding around seven times more tightly than the parent compound JWH-200, though with closer to twice the potency of JWH-200 in activity tests.
AB-001 (1-pentyl-3-(1-adamantoyl)indole) is a designer drug that was found as an ingredient in synthetic cannabis smoking blends in Ireland in 2010 and Hungary and Germany in 2011. It is unclear who AB-001 was originally developed by, but it is structurally related to compounds such as AM-1248 and its corresponding 1-(tetrahydropyran-4-ylmethyl) analogue, which are known to be potent cannabinoid agonists with moderate to high selectivity for CB2 over CB1. The first published synthesis and pharmacological evaluation of AB-001 revealed that it acts as a full agonist at CB1 (EC50 = 35 nM) and CB2 receptors (EC50 = 48 nM). However, AB-001 was found to possess only weak cannabimimetic effects in rats at doses up to 30 mg/kg, making it less potent than the carboxamide analogue APICA, which possesses potent cannabimimetic activity at doses of 3 mg/kg.
ADBICA (also known as ADB-PICA) is a designer drug identified in synthetic cannabis blends in Japan in 2013. ADBICA had not previously been reported in the scientific literature prior to its sale as a component of synthetic cannabis blends. ADBICA features a carboxamide group at the 3-indole position, like SDB-001 and STS-135. The stereochemistry of the tert-butyl side-chain in the product is unresolved, though in a large series of indazole derivatives structurally similar to ADBICA that are disclosed in Pfizer patent WO 2009/106980, activity resides exclusively in the (S) enantiomers. ADBICA is a potent agonist of the CB1 receptor and CB2 receptor with an EC50 value of 0.69 nM and 1.8 nM respectively.
