The CB1 receptor is a tantalizing target for therapies. It is directly involved with many different common disorders and pathologies but most drugs that have been developed to interact directly with this receptor have been found to be intolerable in therapeutic settings. The CB1 receptor is found in high concentrations in the central nervous system (CNS), where it plays a role in inflammation, immune responses, signaling, mood, growth, maintenance, and other essential processes.
It is because of this widespread distribution that synthetic cannabinoids that act on the receptors in the way that bodily cannabinoids do but produce different effects have some negative effects. The main problem is psychoactivity.
This paper presents a novel method of CB1 receptor interaction that could potentially reduce the psychoactive effects of CB1 agonists and antagonist drugs by allosteric modulation, or the indirect influence of CB1 receptors. This less direct way of changing how they interact could increase the beneficial effects of synthetic cannabinoids while reducing the negatives.
The synthetic cannabinoids developed so far are mostly inverse agonists, binding to the receptor in the same way as the body’s cannabinoids but producing different effects, or antagonists, which block or interfere with the ways that the body’s cannabinoids interact with CB1 receptors. This has proved largely unsuccessful due to the psychoactivity this produces when the brain’s CB1 receptors are activated in this way.
The endocannabinoid system is intimately tied in with many other signaling processes in the brain, leading scientists to think that there are more indirect ways of interacting with the CB1 receptor. This is important because the negative effects might be reduced or eliminated but the positives can potentially be increased. Unfortunately, this very complex system is not well understood. Limits of understanding include the shape and interactions of the drugs with the binding sites.
In this paper, the authors explore the new CB1 receptor allosteric modulators, which indirectly influence CB1 receptor interactions. They found one molecule, called here 20, that engaged with other sites that indirectly influenced CB1 receptors without binding to the CB1 receptors significantly. This is a new way of exploring how these interactions occur and a very exciting potential drug for achieving tolerable CB1 activation.
This study is very preliminary work. It has found and highlighted a few potential molecules that have demonstrated indirect modulation of CB1 receptors but the mechanisms and structures are still not clear.
Molecule 20, the molecule that was found to be most effective in this study, binds strongly, possibly irreversibly, to the indirect sites of CB1 influence, which could possibly limit its use. There is no data for human tolerability or effect, so effective therapies using this pathway are a long way away.
Direct CB1 activation has not worked well, so the authors set out to discover indirect ways of interaction with these receptors. They found one molecule in particular did not bind directly to CB1 but did influence how it works. The ground is laid for future research.