There are 6 different types of ligands that bind the CB1 receptor. What is the difference between an inverse agonist and a negative allosteric modulator?

 

The cannabinoid CB1 receptor is one of several receptors that cannabinoids can activate. However, it is perhaps the most important, particularly regarding its effects on mood, cognition, and pain. Activation of CB1 is great if you want to get high, but it’s a mixed bag if you only want pain relief from cannabis.

Cannabinoid CB1 receptor pharmacology - orthosteric and allosteric ligand binding. Agonist, antagonist, inverse agonist, allosteric modulatorWe now have a long list of CB1 ligands (molecules that bind to the CB1 receptor, i.e. cannabinoids) made by the cannabis plant, produced by our own bodies, or synthesized in a lab. Some of these cannabinoids work by activating the CB1 receptor (agonists) and some work by block its activation (antagonists). However, this is an oversimplification – there are actually 6 different classes of ligands.

CB1 is one of the rare receptors to have ligands that fit into every category. Some of these ligands are infamous, such as THC. Others are brand new to the world, being developed to activate the CB1 receptor in a way that does not produce psychoactive effects.

Many people think of CB1 as a light switch that can be turned on by THC and off by CBD. It is more appropriate to think of it as a dimmer switch that can be set to the desired level. This can be accomplished in different ways – either through using cannabis with different THC/CBD ratios or through using a drug from a different ligand class altogether.

There are multiple sites for ligands to bind on the CB1 receptor. There is the main binding site (which is used by THC, CBD, anandamide and most others). This is called the orthosteric site. There are also secondary binding sites called allosteric sites (allo means “other” in Greek). Binding to these sites cannot directly activate the CB1 receptor, but it can induce a conformational change (a change in the shape of the protein structure) that will increase or decrease receptor activation by agonists.

Below are the 6 different classes of ligands and how they work on the CB1 receptor:


1. Full Agonists

Full agonists activate the CB1 receptor to the maximal extent possible. It may surprise many people, but THC is not a full agonist at the CB1 receptor. However, many synthetic cannabinoids, such as HU-210 (found in the now-banned Spice) are full agonists. Notably, ER visits for bad reactions to these synthetic drugs occur at a much higher rate than with cannabis. Full CB1 receptor activation is not desirable due to the side effects.

2. Partial Agonists

Partial agonists can activate the CB1 receptor, but not to the maximal extent possible. THC falls into this category, which means that even at the highest dose you can imagine, it is still not activating the CB1 receptor 100%. This is one of the reasons for the relatively good safety profile of cannabis (the other reason is in the next section).

Here’s an interesting fact: partial agonists and full agonists compete for the same orthosteric binding site on the CB1 receptor. So in theory, if you have taken a synthetic cannabinoid (full agonist) first, then ingesting THC could actually get you less high.

3. Neutral Antagonists

An antagonist will bind to the CB1 receptor at the orthosteric site in a way that it doesn’t activate the receptor, but does block an agonist such as THC from binding. Neutral antagonists do nothing on their own in the absence of an agonist. One example of a neutral antagonist at the CB1 receptor is cannabidiol (CBD). This is why CBD has no psychoactive effects on its own, but it can dampen the psychoactive effects of THC. This story is in reality a little more complicated, since CBD also exerts effects through other cellular targets besides the CB1 receptor, but that is for another article.

4. Inverse Agonists

Many GPCRs have constitutive activity. This means that even in the absence of an agonist, they have some baseline level of signaling activity. The CB1 receptor is no exception. An inverse agonist is a drug that not only blocks agonist binding, but also inhibits this constitutive activity.

Rimonabant is the classic example of an inverse agonist at the CB1 receptor. This drug was approved for a short time in Europe to treat obesity, but was pulled from the market when depression and suicidality were observed.

5. Positive Allosteric Modulators

As explained earlier, the allosteric site is separate from the main orthosteric binding site. Positive allosteric modulators (PAMs) bind this secondary site and amplify the effect of an agonist. They may do this by either increasing agonist binding or increasing receptor signaling.

This is a very active area of research that is receiving funding support from the NIH (they are not as keen to support research on the therapeutic effects of cannabis). The idea is to enhance the “natural” activation of CB1 by endocannabinoids. An example of a PAM is the molecule ZCZ011, which one study showed could reduce neuropathic pain in mice with no observed psychoactive effects.

6. Negative Allosteric Modulators

Negative allosteric modulators (NAMs) are similar to PAMs, except they decrease agonist binding or receptor signaling. A naturally-occurring example of a NAM is pregnenolone, a neurosteroid which a study showed can reduce the effects of THC.

Last modified: May 17, 2017

5 Responses to " Turned On By Cannabinoids – CB1 Receptor Pharmacology "

  1. Miki says:

    In an interview, Dr. Ethan Russoa said:
    “So, cannabidiol is what’s called the negative allosteric modulator, which is a fancy way of saying that when THC is present it interferes with its activity – which is a good thing in terms of wanting too much psychoactivity and again limiting side effects like anxiety or rapid heart rate that can be a problem if someone has too much THC.”

    Can you help to understand which is more accurate? negative allosteric modulator or neutral antagonists?

    https://www.projectcbd.org/article/dr-ethan-russo-cbd-clinical-endocannabinoid-deficiency

    Thank you and very big special thanks for your helpful articles!!!

    • Actually, both are correct! CBD can bind both to the orthosteric site (where it acts as an antagonist) and the allosteric site (where it acts as a negative allosteric modulator). But it only binds weakly to the orthosteric site, so it will only act as an antagonist at high CBD concentrations. At typical CBD concentrations, the NAM activity is the most important.

      I was trying to keep this explanation of different types of ligands as simple as possible, so I presented the “old fashioned” view of CBD. There really is no simple version of cannabinoids though since they act on so many different targets in different ways. I am writing an entire article on THC & CBD mechanisms where I will explain this more in depth, and then I will copy some of that into this post so that there is no confusion.

  2. Jim says:

    Regarding Dr. Ethan Russo’s statement above:
    If cannabidiol’s negative allosteric modulator “limits side effects like anxiety or rapid heart rate” due to too much THC would it not also reduce the psychoactive effects of THC at the same time? If so then his statement is confusing because he states, “which is a good thing in terms of wanting too much psychoactivity…”. Did he leave out the word NOT as in – which is a good thing in terms of NOT wanting too much psychoactivity..?

    Very informative website Prof Of Pot. Thank you for all the hard work. It’s so important to have reliable material on the Net to educate the public.

Leave a Reply

Your email address will not be published. Required fields are marked *