Posted by: Harry | October 31, 2011

Peripherally acting cannabinoid antagonists – a new way to curb hunger?

Discovering and characterizing the active ingredient in marijuana was an interesting challenge. The primary active ingredient, ∆9-tetrahydrocannabinol (THC), was isolated in 1964. THC is a somewhat unusual molecule, at least when compared to the various psychoactive alkaloids that researchers were already familiar with. For many years, there was no known mode of action for these drugs, it was simply assumed that because they were so lipophilic, they caused their effects through some kind of non-specific interaction with cell membranes.

About 20 years ago, two receptors for cannabinoid type drugs were discovered. The first was named CB1, and the second CB2. CB1 is found mostly in the brain, CB2 in the immune system. The question thus became: why should we have cannabinoid receptors at all? What good could they possibly do, given that we presumably did not evolve them just for the sake of appreciating marijuana. But scientists already knew that the brain makes its own morphine, so why can’t it make its own THC too?

Anyhow, it turns out that it does. Several so-called “endocannabinoids” are synthesized throughout the brain and the rest of the body. Their in-vivo functions are numerous, and include regulation of reward function, food intake, and even memory. The relationship with food intake is of particular interest here.

Popularly known as “the munchies”, the relationship between intake of ∆9-THC, one of the main active ingredients in marijuana, and appetite has been reasonably well characterized. As a general rule, exposure to THC makes individuals hungry. While interesting in and of itself, this phenomenon is of great therapeutic interest. On the one hand, dealing with cachexia (a wasting syndrome seen in the later stages of some cancers and AIDS) is a big deal, and few drugs can resolve it satisfactorily, and are as well tolerated as the cannabinoids. On the other hand, the fact that exposure to THC increases appetite, combined with the knowledge that the body possesses an endogenous cannabinoid system immediately leads one to the hypothesis that this system may in fact regulate food intake under normal conditions. After all, if amplifying the effect of the system with an external supply of chemicals increases appetite, perhaps the baseline activity of that system plays a role in ordinary, everyday appetite. It’s only a short leap, then, to the idea that blocking this system and reducing its activity below baseline would lead to reduced appetite, and if you’re someone who is interested in dieting, this is surely a convenient state of affairs.

Thus the quest has been to develop a drug that blocks or attenuates the function of this system just enough to reduce appetite and get one “out of the woods” so to speak. On my next update, I’ll recount in brief the unfortunate tale of rimonabant, a CB antagonist with a lot of promise but also a lot of problems. I’ll also discuss a new paper I read concerning a CB1 antagonist that might avoid some of these troubles.



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