BNC210 (also known as IW-2143 during its time licensed to

Ironwood Pharmaceuticals Ironwood Pharmaceuticals, Inc is a publicly traded pharmaceutical company. It was originally called Microbia, Inc. Microbia was founded by postdocs from the lab of Gerald Fink at the Whitehead Institute to commercialize approaches that had been ...

) is an

anxiolytic An anxiolytic (; also antipanic or antianxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxi ...

drug that acts via negative allosteric modulation of the α₇-nicotinic acetylcholine receptor, by Bionomics Limited. It is currently being investigated for the treatment of

post traumatic stress disorder Post-traumatic stress disorder (PTSD) is a mental and behavioral disorder that can develop because of exposure to a traumatic event, such as sexual assault, warfare, traffic collisions, child abuse, domestic violence, or other threats on a ...

. The drug has demonstrated clinically significant

anxiety Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...

reduction in both

animal models A model organism (often shortened to model) is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the model organism will provide insight into the workin ...

and in Phase I trials. It appears to be devoid of significant sedation or memory-impairing side effects, as well as lacking

addictive Addiction is a neuropsychological disorder characterized by a persistent and intense urge to engage in certain behaviors, one of which is the usage of a drug, despite substantial harm and other negative consequences. Repetitive drug use oft ...

potential in rat discriminatory models. Phase I trials have shown no serious

side effects In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

. Bionomics previously licensed it to

in January 2012, where it was known as IW-2143. In December 2012, IW-2143 begun undergoing phase I clinical trials in the United States, but in November 2014, was released back to Bionomics in a mutual agreement. Bionomics will now continue development and clinical testing, with Ironwood receiving a royalty for their work done. In April 2015, BNC210 was in phase II

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...

s. The estimated study completion date was September 2018. In October 2018, the company announced that the candidate failed to meet its primary endpoint in treating PTSD but may have shown some anti-depressant and anxiolytic effects (the phase II trial's secondary endpoints). The drug is still being developed and secured

Fast Track The fast track is an informal English term meaning "the quickest and most direct route to achievement of a goal, as in competing for professional advancement". By definition, it implies that a less direct, slower route also exists. Fast track or F ...

designation from the FDA based on the drug's novel mechanism of action and the 'large unmet need with PTSD' in the community. There is a large unmet need for efficacious anxiolytics which do not have the habituation, dependency, sedation, tolerance, and intoxication issues with current generation

Mechanism of action

There is little information on BNC-210, but it may be a GABA antagonist based on an abstract released, though it is unclear if the abstract is referring to this compound or related compound. This is somewhat counter-intuitive, as generally, GABA antagonists would produce anxiogenic effects. The only mention here is that there was a discussion 'anxiolytics and GABA agonists' which included BNC-210, but does not specify that BNC-210 is of the latter. Most relevant here is the date, 2009 appears to be the first time the drug appeared in the readily searchable literature. It is a negative-

allosteric In biochemistry, allosteric regulation (or allosteric control) is the regulation of an enzyme by binding an effector molecule at a site other than the enzyme's active site. The site to which the effector binds is termed the ''allosteric site ...

modulator of the

alpha-7 nicotinic receptor The alpha-7 nicotinic receptor, also known as the α7 receptor, is a type of nicotinic acetylcholine receptor implicated in long-term memory, consisting entirely of α7 subunits.Pharmacology, (Rang, Dale, Ritter & Moore, , 5th ed., Churchill Liv ...

. It binds at a site distant from the traditional

nicotine Nicotine is a natural product, naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and ''Duboisia hopwoodii'') and is widely used recreational drug use, recreationally as a stimulant and anxiolytic. As ...

binding site for which this receptor is named, (binding

acetylcholine Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Part ...

in-vivo), and decreases the activity of the ligand gated ion channel. This has downstream effects, similar to, inhibition at this site. Acetylcholine, while being used very widely and commonly in mammals, is especially prominent in the function of memory and

Long-Term Potentiation In neuroscience, long-term potentiation (LTP) is a persistent strengthening of synapses based on recent patterns of activity. These are patterns of synaptic activity that produce a long-lasting increase in signal transmission between two neurons ...

. The authors cite the drug's activity in the

amygdala The amygdala (; plural: amygdalae or amygdalas; also '; Latin from Greek, , ', 'almond', 'tonsil') is one of two almond-shaped clusters of nuclei located deep and medially within the temporal lobes of the brain's cerebrum in complex verteb ...

, which is the seat of

fight-or-flight The fight-or-flight or the fight-flight-or-freeze response (also called hyperarousal or the acute stress response) is a physiological reaction that occurs in response to a perceived harmful event, attack, or threat to survival. It was first des ...

and emotional responses and thought to be the source for unpleasant symptoms felt by those who have been exposed to particularly strong negative emotional states (

Traumatic Stress Traumatic stress is a common term for reactive anxiety and depression, although it is not a medical term and is not included in the ''Diagnostic and Statistical Manual of Mental Disorders'' (DSM). The experience of traumatic stress include subtypes ...

leading to

PTSD Post-traumatic stress disorder (PTSD) is a mental and behavioral disorder that can develop because of exposure to a traumatic event, such as sexual assault, warfare, traffic collisions, child abuse, domestic violence, or other threats on a ...

. It should be stated, that the authors present no evidence of the drugs (specific) activity in this location, and it should be considered one proposed mechanism of action. The study's authors did do fMRI imaging that may show diminished responses in this brain area, but the small sample size and other limitations to fMRI imaging apply here and outside the scope of this article. The basis for this is the observation of the proposed mechanism of PTSD and the locality of this receptor, in addition to cellular studies on transfected rat and human cells, leads to this proposed mechanism of action. The α7 subtype of the Nicotinic Acetylcholine is heavily represented in the amygdala (along with the mammary bodies (brain structure), and Ammon's horn. With respect to fMRI data, the drug had a more pronounced effect at the low dose, reportedly on par with Lorazepam, while the high-dose was most similar to Placebo. This should not be at all interpreted that the effects are even remotely related to those of

Lorazepam Lorazepam, sold under the brand name Ativan among others, is a benzodiazepine medication. It is used to treat anxiety disorders, trouble sleeping, severe agitation, active seizures including status epilepticus, alcohol withdrawal, and c ...

, only that the effect on suppression of this small, particular part of the brain is similar, in simply a measure of metabolic activity. The study included only 24 participants, in 4 arms, so drawing major conclusions from the paper is not wise, but it at least provides additional evidence of possible

efficacy Efficacy is the ability to perform a task to a satisfactory or expected degree. The word comes from the same roots as ''effectiveness'', and it has often been used synonymously, although in pharmacology a pragmatic clinical trial#Efficacy versu ...

References

{{Tryptamines Dipeptides Anxiolytics Nicotinic antagonists Experimental drugs

Mechanism of action

See also

References