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TSPO Ligands For Anxiety: Targeting the Peripheral Benzodiazepine Receptor

Just recently researchers were able to unveil the crystallized structure of translocator protein. It has long been thought that various polymorphisms of the TSPO gene create dysfunctional variations of the translocator protein (18 kDa). The 18 kDa translocator protein is hypothesized to contribute to certain mental illnesses, particularly anxiety disorders.

The newly discovered crystallized structure should allow researchers to get a better understanding of how various drugs interact with TSPO. This brings hope that scientists could potentially create drugs that correct functional TSPO abnormalities, leading to a healthier expression of the translocator protein (18 kDa). Without getting too caught up in TSPO, just know that its basic functions include: binding to cholesterol and binding to drugs; the latter will be discussed.

TSPO Ligands: List of Drugs

Any substances that elicit function (directly or indirectly) by binding to the “perhipheral benzodiazepine receptor” are TSPO ligands. A very popular indirect TSPO ligand is that of Valium (Diazepam), a drug classified as a benzodiazepine, that also elicits an effect on TSPO. There are also new investigational substances that elicit more of a targeted or “selective” effect on TSPO.

Emapunil (AC-5216/XBD-173)

This is considered an anxiolytic drug that functions as a selective agonist at the peripheral benzodiazepine receptor a.k.a. TSPO. Based on research among animals and humans, Emapunil administration resulted in significant anxiolytic effects with zero sedation or withdrawal following usage. In addition to functioning as an anxiolytic drug, Emapunil also is used as a radioactive tracer to identify TSPO receptors within the human brain.

Emapunil seems to induce neurosteroidogenesis, leading to enhanced neurotransmission of GABA, a neurotransmitter associated with relaxation and calmness. Unlike benzodiazepines, it doesn’t directly affect the GABA receptors, hence being considered to target “peripheral receptors.” Based on early research, it should be speculated that this drug is likely favorable over benzos in that it doesn’t trigger sedation, has less side effects, and works very quickly.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/21609361
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/24397957

DAA-1097

This is a drug that acts on TSPO or the “peripheral benzodiazepine receptor,” leaving central benzodiazepine receptors unaffected. In animal studies, it has been found to produce significant anxiolytic effects. Unfortunately there isn’t much research available regarding this particular ligand. Some have suggested that it be further tested to determine whether it could make a potentially good treatment for anxiety disorders.
Source: http://www.ncbi.nlm.nih.gov/pubmed/10321725

DAA-1106

This TSPO ligand functions as a selective agonist at the peripheral benzodiazepine receptor and doesn’t affect any of the central benzodiazepine receptors. In animal studies, it demonstrates clear anxiolytic properties and is often used in its radioactive format to label TSPO in the brain (during brain scans). It has been considered very helpful in labeling of TSPO in brains among individuals with neurodegeneration (i.e. dementia).

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/16842193
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/18790550

FGIN-127

This is a drug that functions as a selective agonist of the PBR (peripheral benzodiazepine receptor). It tends to act primarily as an anxiolytic drug via stimulation of steroidogenesis. The steroidogenesis associated with FGIN-127 leads to increased levels of neuroactive steroids like allopregnanolone (ALLO).

The allopregnanolone then tends to modulate the GABAergic activity within the brain via action on receptors. Some have classified FGIN-127 as belonging in a subtype of TSPO ligands known as “indoleacetamides.” Whether researchers will investigate this particular drug in humans remains unknown, but is unlikely.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/16842193

FGIN-143

This is an anxiolytic drug similar to FGIN-127, except it is believed to be significantly more potent. Some speculate that FGIN-143 is approximately 3x as potent of an anxiolytic as FGIN-127. It has the same mechanism of action though and acts as a selective agonist at TSPO (peripheral benzodiazepine receptor).

It then stimulates the process of steroidogensis which increases levels of neuroactive steroids (i.e. allopregnanolone) and GABAergic transmission is affected, leading to increased relaxation. Thus far this substance appears to have been studied in rodent populations with success at reducing anxiety.
Source: http://www.ncbi.nlm.nih.gov/pubmed/11732760

PK-11195

This is a TSPO ligand that is classified as an “isoquinoline carboxamide.” It functions by selectively binding to the PBR (peripheral benzodiazepine receptor). It also tends to bind to various other sites within the nervous system of rodents and elevated levels of binding are frequently seen among those with CNS injuries. In addition to producing an anxiolytic effect, it is also utilized in radioactive form to as a biomarker for detection of brain damage and/or neurodegenerative diseases.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/19075709

Ro5-4864

This is a substance derived from Valium (Diazepam) and functions differently compared to most benzodiazepine derivatives. What separates Ro5-4864 is that it has no affinity for GABA receptors, ultimately leading to different effects (in comparison to a benzodiazepine). Oddly enough, it’s actually a TSPO ligand that you would NOT want to use if you had anxiety, as it is known to increase it.

Although it is a very potent ligand for the PBR (peripheral benzodiazepine receptor), it also tends to result in convulsions (another counterintuitive effect). When taken at low doses, some believe it is a neuroprotective agent, and has been used in research to investigate its ability to prevent excitotoxicity. In rodent studies, documentation reveals that the drug may act as an anticancer, antidepressant, and/or cardioprotective agent.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/15696538

SSR-180575

This drug acts as a selective agonist at the PBR (peripheral benzodiazepine receptor). It is believed to function by stimulating steroidogenesis in the brain, leading to increases in essential neuroactive steroids. It is the neuroactive steroids (e.g. pregnenolone) that elicit neuroprotective and cardioprotective effects. This substance was more heavily investigated in the early 2000s, but as of now, research seems to have drastically slowed.

Benzodiazepines that affect TSPO

Several benzodiazepines bind to the PBR, most notably Valium. However, most consider benzodiazepines as having indirect effects as TSPO ligands compared to the substances listed above.

Rohypnol (Flunitrazepam)

This drug is considered a benzodiazepine, but is thought to have equal action on GABAA receptors as well as peripheral benzodiazepine receptors (PBR). When administered, it tends to produce feelings of relaxation, sleepiness, drowsiness, and muscle relaxant effects. It is considered to have very significant hypnotic (sleep-inducing) properties.

Valium (Diazepam)

Unlike the other TSPO ligands listed here, Valium is classified as a benzodiazepine drug. It elicits an anxiolytic effect by acting on both the GABAA receptor as well as the PBR (peripheral benzodiazepine receptor). Some have gone as far as to suggest that Valium binds equally well to the central benzo receptor as it does to the peripheral receptor.

In any regard, this drug has been around for a long time and is still frequently used for the treatment of temporary anxiety, panic, insomnia, seizures, and various drug withdrawals. Since it affects the central benzo receptor, it has a propensity to cause dependence, addiction, drowsiness, and possibly long-term memory impairment.

Versed (Midazolam)

This is a short-acting benzodiazepine drug that has been around since the 1970s. It is most often utilized as a sedative prior to medical procedures, but can be used to treat insomnia and anxiety. It is among the most common benzodiazepines used specifically for the purposes of medical sedation. Although it is functionally classified as a benzodiazepine for its influence upon GABAergic neurotransmission, it also affects the peripheral benzodiazepine receptor (PBR).

Potential advantages of TSPO ligands for anxiety disorders

TSPO ligands can be utilized to treat a variety of conditions, but from a psychiatric perspective, they are known most for their anxiolytic properties. Although there are several new anxiety medications in 2015 that are under development, it is thought that TSPO ligands will be further investigated in the coming years specifically for treating anxiety.

The reason they will be further investigated is due to the fact that benzodiazepines are problematic for numerous reasons. Most experts would argue that long-term usage of benzodiazepines is bound to cause more harm than benefit. Mounting evidence continues to highlight the fact that dementia is linked to benzodiazepines and other sedatives that directly target GABAergic neurotransmission.

  • Addiction potential: TSPO ligands appear to have less addiction potential than standard benzodiazepines. The potential for addiction is likely mitigated by the fact that they don’t directly affect GABAA receptors.
  • Dependence: There is also less likelihood that a person will develop dependence on a TSPO ligand in comparison to a benzodiazepine. Should an entire class of TSPO ligands for anxiety get developed, they will likely replace benzodiazepines for those with severe anxiety.
  • Long-term effects: The long-term effects of taking TSPO ligands remains relatively unknown. However, it should be speculated that since they don’t directly target central benzo receptors, they are unlikely to cause as significant of impairment over the long-term.
  • Neuroprotective: There is some evidence that certain TSPO ligands have neuroprotective effects in rodents. Obviously this doesn’t mean that there would be carryover to the brains of humans, but it does mean that there’s potential. Should a ligand get developed that treats anxiety as well as acts as a neuroprotective substance, it would become frequently used.
  • Rapid-acting: These ligands don’t tend to take a significant amount of time to work, they generally work immediately. Most consider them to be just as rapid-acting as benzodiazepines. The rapid anxiolytic effect is often preferred by those with insomnia and severe forms of anxiety.
  • Side effects: Most evidence points to the fact that TSPO ligands tend to have less detrimental side effects in comparison to benzos. People taking anxiolytic drugs don’t want to feel dizzy, disoriented, and/or sleepy all throughout the day. It seems as though by targeting the peripheral benzo receptors, sedative and hypnotic effects are reduced, while anxiolytic effects remain.
  • Withdrawal: In preliminary testing of certain substances, no withdrawal symptoms were observed. Benzodiazepines can be troublesome in that users often are plagued with long-lasting, tortuous withdrawal symptoms, including significant rebound anxiety. Although TSPO ligands will likely have withdrawals, it should be of less severity than that of benzos.

Although TSPO ligands may be safer and equal in efficacy to benzodiazepines for the treatment for anxiety, the safety cannot be verified. Despite preliminary rodent and animal studies highlighting the positive properties of these substances, it is important to remain skeptical of their safety over the long-term. Until more novel, selective TSPO ligands are developed and actually tested in humans, we won’t know how a person will react.

Bottom line: New TSPO ligands warrant testing

It should be thought that TSPO ligands will be safer in comparison to benzodiazepines in that they don’t directly affect the GABAA receptor. As technology continues to improve, it is likely that pharmaceutical companies will work with researchers to create novel, selective ligands of TSPO, especially now that they have identified the crystallized structure.

Logic would suggest that there should already be at least one selective TSPO ligand on the pharmaceutical market, but there isn’t. The closest TSPO ligand to actually being utilized for the treatment of anxiety disorders was Emapunil, but its development appears to have been squandered. Most of the current focus is spent using these ligands in PET scans to identify areas of the brain with neurodegeneration, but in coming years, that may change.

  • Source: http://www.nature.com/nrd/journal/v9/n12/fig_tab/nrd3295_T2.html

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