Synthetic THC Analogs and Synthetic Cannabinoids

The first analogs of THC were created in the 80’s and were known as CP-47,497 and HU-210. Once these analogues were created, the response began to bring on more research, which by the early 90’s CB1 and CB2 were discovered. CP-47,497 showed cannabimimetic actions of depressant motor skills, analgesic, hypothermic effects, anti-convulsant and when used on dogs increased their vocalization.

One independent search for anti-nociceptive compounds that were based on NSAID’s that were known announced iaminoalkyl known, as indoles were distinct structurally such as WIN 55,212-2. This indole binds both CB1 and CB2 with much stronger similarity than THC. John Huffman led the team that discovered this while working at Clemson University, which resulted in simple modeling that an alkyl chain was able to replace the aminoalkyl group. More investigations resulted in hundreds of JWH chemical compounds showing the binding similarities for CB receptors.

One prototypical JWH chemical compound is JWH 018. This compound offers a very strong potency and non-THC structure, which made it quite desirable for the creation of several Spice/K2 like herbal blends. A good example of this is an herbal compound that was marketed as incense and was not intended for human consumption contained several synthetic CB’s such as JWH 073, JWH 018 or in some cases CP 47,497 along with natural endocannabinoids and other substances such as a-tocopherol.

In the United Kingdom, the Advisory Council on the Misuse of Drugs created generic legislation that would control all synthetic CB’s, created a structural classification of all JWH chemical compounds.

In the UK, the groups and examples of compounds include:
Group 1: naphthoylindoles includes JWH 018 and 73 other chemical compounds.
Group 2: naphthylmethylindoles includes JWH 175 and eight other chemical compounds.
Group 3: naphthoylpyrroles are very strong CB receptor agonists, which include JWH 147 and have a high abuse potential along with 31 other chemical compounds in this same group.
Group 4: napthylmethylindenes includes JWH 176 and two other compounds.
Group 5: phenylacetylindoles includes JWH 203 along with 27 other synthetic CB’s that have been discovered in herbal blends.

Several THC analogs and first generation synthetic CB’s have been regulated by countries across the globe such as HU-210, CP 47,497, JWH 018 and JWH 073. Of course, these have now been replaced by other JWH chemical compounds that are very potent, which include naphthoylindoles, which includes JWH 398, JWH 210, JWH 200, JWH 122, and JWH 081 and phenylacetylidoles like JWH 251, JWH 250, and JWH 203. Along with this, chemical compounds known as AM-type chemical compounds like AM2201 has been found in a patent by Alexandros Makriyannis. The patent announces benzoylindoles such as AM679.

Another scientist, Abbott, included a tetramethylcyclopropyl group, which includes UR44 to give selectivity for the CB2 receptor. Even though this chemical compound is selective for CB2 it still binds CB1 efficiently, which explains why it is very popular.

The report by Abbott and the patent by Makriyannis explain several different chemical compounds that are good candidates for abuse.

Many different synthetic CB’s have unique structures. One such example is AZ-11713908, which has a benzimidazole core instead of an indole core, which is found with the JWH CBs, but provides momentous CB2 selectivity.

Other chemicals compounds that have similarities for CB receptors along with effectiveness in vivo have a quinolone core.

Another with a quinolone base in the adamantylamino group is SER-601 provides more selectivity for CB2 instead of CB1. This group of compounds is among the newer synthetic CB’s which is replacing naphtyl compound groups like AM2201 and JWH 018 to create STS-135 and 2NE1, respectively.

The combination of a thiazolylidene base and a tetramethylcyclopropyl group base gives A836, 339, which, even though it is CB2-selective it also activates CNS CB1 in vivo at higher doses. A836,339 combines neuronal pain suppression through CB2 with less psychoactive effects via CB1 from the synthetic cannabinoids with higher similarities for CB1.