Cannabinoid agonist JWH-018 (part 1)

[another repost in a 2-part series, but this time because the topic is very much in demand lately. -leigh]

I’ve been noticing lots of talk of these “new” synthetic cannabinoids floating around out there lately, now that Spice and K2 have gotten a lot of media coverage. I also found a lot of hearsay and uninformed opinion floating around on the internet in various places, but not so much of the scientific information. Let’s remedy that, shall we? I’ll cover the basics over a couple of posts and more if there are remaining questions.

Spice and K2 are being floated as the new “legal marijuana” – a supposedly marijuana-like high without legal consequences. Abel Pharmboy kicked off the discussion with a Research Blogging post about synthetic cannabinoids that you should definitely check out. DrugMonkey brought up an interesting thought in his post on the topic: does the US Controlled Substance Analogue Enforcement Act of 1986 apply? This act states (I paraphrase here) that a compound that shares a similar chemical structure or pharmacological action and is intended for human consumption is treated as a Schedule I classified drug. According to some interpretations of people who know more about legal stuff than I do, that might be a negative. So let’s explore the chemistry of the cannabinoid agonists** to get started.

**Disclaimer: I am not an organic chemist. Don’t crucify me.

Delta-9 THC, the principal psychotropic ingredient in marijuana, is a terpenoid compound produced by the Cannabis sativa plant. You can examine its structure here:

Figure 1. THC chemical structure (via Pubchem)

THC acts through brain cannabinoid receptors to produce its typical effects. However, those receptors are involved in a whole lot more than just producing the psychotropic effects of cannabis intoxication. The pursuit of understanding the mechanism of action of cannabinoids, as well as further research to better understand the normal and abnormal physiology of the endogenous cannabinoid signaling system, has resulted in many novel synthetic drugs designed to target the cannabinoid receptors in experimental systems. They were devised to be used as tools to elucidate what happens when we probe the system- for instance, what molecular properties are required for a given drug-receptor interaction property (efficacy, affinity, what have you).

There are multiple classes of structurally distinct cannabinoid agonist drugs that emerged from these efforts. Given the topic under discussion here, I will focus on the aminoalkylindoles. They are structurally unrelated to delta-9 THC, as you can gather by the structure.

Figure 2. Aminoalkylindole cannabinoid agonist WIN55,212-2 structure (also via Pubchem)

Here’s where I bring in the so-called “legal marijuana” – one of the compounds that’s causing this stir, named JWH-018, is a derivative of the aminoalkylindole class of drugs. Take a look for yourself, and consider the similarities to the aminoalkylindole above.

Figure 3. JWH-018 structure. Rotated (imperfectly, but you get the idea) to demonstrate structural similarity to figure 2.  Pubchem may be a good start, but how about we get something that lets us rotate around bonds? Get on that, NCBI.

Note again that these are synthetic compounds- they are not analogs of THC and not produced by the Cannabis sativa plant. They are structurally unrelated, but act upon the same receptor as does THC. They have different pharmacological properties: efficacy and potency, which I will discuss in the next post. This does not make them “better” in some or any way compared to the plant-derived cannabinoid compound.

Now the curious thing is that while these synthetic classes of compounds may be structurally distinct from the original cannabinoid compound of interest, they do produce pharmacological effects that are classified as cannabimimetic. And yet, one does not need a DEA license to obtain some of these research chemicals.

Many of these “legal” products are distributed as plant matter soaked in JWH-018 and other compounds, and then marketed as incenses- covered with warnings about how they are not intended for human consumption. This is also curious. How long will this hold off the inevitable? I don’t have a guess.