What is Allosteric Modulation?

This phenomenon plays an important role in psychedelic drug research and development.

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G protein-coupled receptors (GPCRs) are at the heart of psychedelic science. All the serotonin receptors, such as 5-HT2A, are GPCRs. The exception is 5-HT3, which works via ligand-gated ion channels.1 A more in-depth look at receptors is found in the Psychedelic Science Review article Cellular Receptors and Their Role in the Psychedelic Effect.

Woven into the functioning of GPCRs is a little-understood concept that has profound implications in psychedelic research and drug development. Understanding the phenomenon known as allosteric modulation (or modulator) (AM) is essential for getting the full picture of GPCR functioning and potential. The idea of an allosteric site was first coined by Monod et al. in 1962.2

On the surface, the mechanics of AM sound simple. A ligand binds at a site on a receptor (the allosteric site) other than the orthosteric (primary) binding site.18 Or, as the International Union of Basic and Clinical Pharmacology explains it, an AM is,3

A ligand that modifies the action of an orthosteric agonist, endogenous activator, or antagonist by combining with an allosteric site on the receptor macromolecule.

Types of Allosteric Modulation

The binding of an AM to a receptor causes conformational changes in the amino acids that make up the receptor structure. Also, other alterations in the receptor state and downstream signaling can occur. These alterations change how the receptor interacts with the orthosteric ligand, an agonist, or antagonist.

There are basically three types of AM:4

  • Positive (PAM) – These ligands increase the affinity, efficacy (responsiveness), or both of the receptor for the orthosteric ligand.
  • Negative (NAM) – This type of ligand decreases the affinity, efficacy, or both of the receptor for the orthosteric ligand.
  • Neutral (aka SAMs, silent allosteric modulators) – These ligands don’t affect the activity of the orthosteric ligand. However, they can stop other compounds (including other modulators) from binding to the orthosteric site.

Targeting allosteric sites on GPCRs presents many opportunities for drug exploration. Although AM is not unique to GPCRs, they are by far the largest class of targets for modern-day drugs.5

Allosteric Modulation, Psychedelics, and the Entourage Effect

When it comes to the entourage effect in naturally occurring psychedelic cocktails, allosteric modulation adds another deep layer of complexity and mystery for scientific study. For example, what is the role of AM in The Entourage Effect in Magic Mushrooms? Other naturally occurring organisms containing psychedelic compounds such as kratom, ayahuasca, cannabis, and ibogaine pose the same question. More understanding of the mechanisms involved will make it possible to create formulations with precise amounts of purified compounds.

The literature reveals some intriguing findings about AM and its possible application to psychedelic drug discovery development. This remains a wide open area for study for the curious researcher.

A protein known as mGlu2R (metabotropic glutamate receptor 2) is a GPCR that is highly expressed in areas of the brain that are implicated in schizophrenia such as the prefrontal cortex, striatum, thalamus, amygdala, and hippocampus.6 mGlu2R is often a target for PAMs in the treatment of schizophrenia.

In a 2015 review paper, Ellaithy et al. discuss studies indicating there is “crosstalk” between mGlu2R and 5-HT2A receptors.7 They wrote, “Interestingly, mGlu2R has been shown to be necessary for pharmacological and behavioral effects induced by hallucinogenic 5-HT2A agonists…” Further work done in 2016 collaborates this observation.8,9

Ellaithy et al. concluded,

Collectively, these data suggest that a common target for psychedelics, atypical and glutamate antipsychotics is the 5-HT2A–mGlu2R complex, for which designing a bivalent ligand might be a rational therapeutic strategy.

In a 2009 review paper, Conn et al. discuss the experimental evidence for treating central nervous system disorders with AM of GPCRs.10  They express their optimism for the research path by saying, “The major advances in discovery and characterization of novel GPCR modulators are providing fundamental new insights into the mechanisms of action, range of activities and keys to chemical optimization of these compounds as therapeutic agents.”

Research on allosteric modulation in cannabinoid compounds is yielding interesting information as well. For example, in 2005, Price et al. discovered that the cannabinoid CB1 receptor has an allosteric binding site.11 Also, a 2015 study done by Laprairie et al. found that the cannabinoid cannabidiol is a negative allosteric modulator of CB1.12

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