Anandamide (You can put your weed in it!)
2nd June 2006
When cannibis was first being studied, the active principle was isolated and found to be delta-9-tetrahydrocannabinol, shown below. Later on, studies showed that there were, in fact, endogeneous receptors that interacted with the compound. In abundance. We termed it the cannabinoid receptor, for lack of a better word. Endogeneous or not, the only thing we knew that would fit in it came from a drug of abuse!
This was baffling: Nature tends to be pretty parsimonious. A truly vestigial receptor class was unlikely. So did we evolve in the (continuous) presence of dope fields? Surely not. This was a strong indication that there was some sort of endogeneous cannabinoid. The search was on. Despite having known about marijuana for literal millenia, we didn’t find an endogenous ligand until 1992! This came out of Raphael Mechoulam’s lab - the same guy who isolated THC back in 1964! To be fair, even though THC was long-since discovered, we only knew about cannabinoid receptors as recently as 1988.
I won’t even attempt to elucidate any real similarities. They look nothing alike to my (admittedly non-medicinal chemistry trained) eyes. Anandamide is a big floppy thing (non-cyclic compounds always flop around like tiny whips in solution, with a few exceptions, like proteins; the peptide bond is rigid). THC is a mostly rigid ring system (six membered rings wiggle a bit, but that’s about it). One is aromatic, one is nonconjugated (alternating double and single bonds mean a molecule exhibits a phenomenon called conjugation, which can be important for enzyme binding). Aside from lipophilicity and a hydrogen-bond acceptor and donor similar distances from one another in the molecule, they seem as different as can be.Cannabinoids show some promise as painkillers. We don’t have this pain business figured out quite yet. As enjoyable as you may find your post-dentist vicodin, someone else will find it makes them vomit. Not to mention the addictive potential. And constipation. While not completely benign in their own right, cannabinoids seem as though they make be able to induce analgesia at subpsychoactive doses.
Most painkillers you will encounter are either opioids or COX inhibitors. Acetaminophen is a notable exception. Substance P looked promising for awhile, but it seems more and more like we’re hitting a dead end.
It will probably be some time before you see a cannabinoid painkiller, and the first one to market will have a huge hurdle to jump. I don’t count marinol, which is just THC in oil, since it’s a natural product that has been used for millenia. Although we know it’s not exactly chamomile tea, thousands of years of people using it and not sprouting horns goes a long way toward approval of a drug. A first-in-class drug targeting a poorly understood pathway will probably hit some snags.
Enjoy the weekend. See you Monday.