CB1 Cannabinoid Receptor Modulation Using Allosteric Ligands

Written by Yahav Blaicher

Understanding the world of cannabinoids began in the mid 60s, when Doctors’ Mechulam and Gaoni discovered various compounds, like tetrahydrocannabinol (THC) and Cannabidiol (CBD) in the 90s. In the last 50 years numerous studies have aimed to understand the endocannabinoid system, whose main components are cannabinoids receptors and the endocannabinoid ligands that bind to those cannabinoid receptors.

Cannabinoid receptors have been shown to be key regulators of nausea, obesity (1;2), pain (3;4), anxiety, depression, substance-use disorders (5) and neurodegenerative disorders such as Alzheimer’s disease (6), and Parkinson’s disease (7). And now scientists and researchers are looking into CB1 Cannabinoid Receptors to see what role they really play.

In this article we will review research on CB1 Receptor from the Universities of California, Indiana and Connecticut, who studied the regulation of cannabinoid receptors and discussed potential therapeutic agents for the treatment of multiple psychiatric and neurological disorders in humans.

The CB1 receptors are primarily located on nerve cells in the brain, especially in the cerebellum, basal ganglia, hippocampus and the spinal cord regions. For this reason, cannabinoids can affect functions such as memory processing, pain regulation and motor control. Nonetheless, CB1 receptors may also be found in tissues such as the spleen, white blood cells, endocrine gland and parts of the reproductive, gastrointestinal and urinary tracts..

The CB2 receptors are bounded to white blood cells, Gastrointestinal Tract and immune cells also express the CB1, but yet less than CB2. Cannabinoid receptors in the immune system are responsible for a very important area- the regulation of cytokine .

Traditionally pharmaceutical researchers focused on the “target site” of active compounds in order to discover new medications. The developed medicinal drug product is usually a small organic molecule (ligand), man-made, natural, or endogenous, that activates or inhibits the function of a biomolecule such as a protein. The drug is complementary in shape and charge so it can interact with the biomolecular target and achieve a biochemical or physiological effect on the cell, which results in a therapeutic benefit for the patient.

In general, biochemical reactions occur at the target site of protein, while the velocity and efficiency of the reaction depends on the affinity of the small molecule to the target site. Sometimes the cell needs to regulate and control this activity, in what is called allosteric regulation, in which the protein binds an effector molecule at a site other than the active site. The term allostery comes from the Greek words allos (other) and stereos (location). Binding to an allosteric site often results in changes to the protein conformation and thus it affects its dynamics too. Effectors that enhance the protein’s activity are referred to as allosteric activators, whereas those that decrease the protein’s activity are called allosteric inhibitors.

This mechanism works as well for receptors in the central nervous system. Receptors are proteins located on the cell membrane and who receive chemical signals from outside a cell. When such chemical signals bind to a receptor, they trigger a cellular response (for example, activating neurons by their own receptors is the primary way to explain information transfer in the brain).

G protein coupled receptors (GPRC) are a predominant group of receptors found in most living organisms. A typical GPRC protein complex is composed of a few compartments that pass through the cell membrane several times. The exocellular parts detect molecules outside the cell and activate internal signal transduction pathways that eventually give rise to cellular responses.

CB1 receptors are GPRC and as such, activated by two major groups of ligands: the endocannabinoids, generated naturally by mammalian body and the phyto-cannabinoids, which are introduced into the body from cannabis or a synthetic cannabinoid compound. These cannabinoids have different affinities to the CB1 receptors, thus conventional drug development can create ligands that can compete with the endogenous cannabinoid, primarily by targeting the active site (orthosteric site) of the cannabinoid receptors.

If CB1 receptors were proven to regulate so many signals in our brain, why are there only 3 cannabinoids clinically approved for therapeutic use? (8;9;10). Some molecules that naturally bind to CB1 receptors with high affinity cause psychoactive side effects.. The reason is that high expression of CB1 in the brain (5) may lead to highly neuron excitement.

To detect and quantify allostery at CB1 receptors, the scientists used binding assays, which defined the impact of the allosteric modulator and cannabinoid on each other when both occupy the receptor. Another method used was measuring the cellular response in the presence of cannabinoid and allosteric modulators (13).

In this work Khurana and colleagues reviewed previous research on CB1 allosteric modulators. The drug ORG27569 developed by Merk acts as a potent modulator that binds to a regulatory site on the CB1 receptor, causing cannabinoids to be more effective on CB1. Likewise, ORG27569 blocks the effect of CB1 suppressors. PSNCBAM-1 in contrast is a negative CB1 modulator. The researchers showed, in a rat model, that PSNCBAM-1 interfere with the neuronal effects of CB1, and caused decrease in both food intake and body weight gain (14).

Some scientists claim that the therapeutic potential of allosteric modulators of the CB1 receptor is promising. PSNCBAM-1, for example, elicits acute hypophagic effects (14) and may lead to treatments of obesity and some central nervous system (CNS) disorders or treat drug addiction. Pregnenolone is blocking the psychotic-like symptoms such as THC-impaired cognitive function (21). Lipoxin A4 has been shown to protect neuronal cells from b-amyloid-induced neurotoxicity (15), thus demonstrating possible therapeutic potential for the treatment of Alzheimer’s disease. Other may treat neuropathic pain (22).

The authors conclude their work by stating that CB1 is diverse in shape and function in many sites of the brain, hence its allosteric modulators hold new opportunities to develop therapeutics that are subtype-specific and in some cases, pathway-specific and can be utilized for the treatment of human diseases.

Further identification of the allosteric binding sites, the authors say, may bring to design of small molecules for efficacy and safety optimization.


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[Featured image credit: Pixabay]

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About the author

Yahav Blaicher