All three neutrotransmitters are known to play important roles in numerous neuronal processes - including mood, anxiety, stress responses, cognition, attention, sex, urinary flow, pain, impulse control, reward and arousal.  Based on these roles, enhancing their transmission is thought to be a sound approach to treating abnormalities in these processes.

   Although each neurotransmitter is thought to have a primary effect on its 'target' domain, there is significant overlap on certain domains like mood and cognition which can lead to broader treatment effects and greater efficacy.  There is clear evidence for 'crosstalk' amongst the 3 neurotransmitters.  Crosstalk is the interaction of the 3 with one another mediated by heterologous receptors which facilitate or inhibit neurotransmission of the 3 neurotransmitters.  In other words, there can be a synergy/additivity to the interactions,

   It has been hypothesized that the addition of dopamine effects which is involved, in pleasure, motivation, and reward may also speed response, reverse anhedonia and anergia, and not produce sexual dysfunction as found with SSRIs. Animal models of sexual function have shown that chronic SSRI treatment cause sexual dysfunction, but chronic TRI treatment did not alter sexual function. Thus, the multifunctional effects of TRIs may enhance efficacy and mitigate some adverse events such as sexual dysfunction   
   Simply put, a TRI creates multiple shots on the same goal, while at the same time potentially offering additional benefits with respect to effectiveness and tolerability.

Chemical structures and pharmacology  
    The pyran based TRI’s were discovered and synthesized by Dr. Aloke Dutta at Wayne State University and are now exclusively licensed to TRImaran Pharma Inc. The unique pyran chemical platform is readily amenable for asymmetric syntheses. Over 100 pyran TRI’s have been synthesized and evaluated for their structure-activity relationship (SAR). This extensive evaluation program led to compounds with variable ratios of affinity for the three transporters resulting in several distinct potential therapeutic indications. These compounds have high affinity for 5-HT, NE, and DA while exhibiting low affinity for neuronal receptors resulting in a relatively low likelihood of adverse events due to off-target activities. They also have biological activity, long half-lives, and good brain penetration in animals. For example, the Ki values for the lead compound D-473 for uptake by human transporters were 9.2, 40, and 70 nM for 5-HT, NE, and DA, respectively (Dutta et al., 2014).
Patent Status
    TRImaran Pharma Inc. has exclusively licensed the patents for the pyran compounds from Wayne State University. The patent expiry date, with extension, for these drugs is 2033.
Development plan
    TRimaran Pharma Inc. has moved three of these lead compounds to full developmental status and are ready for IND-enabling toxicology studies.  Compound D-473 which has highest affinity for serotonin and norepinephrine will be targeted initially for PTSD and MDD. A second compound seems ideally suited to treat ADHD as it has high affinity for NE and lower affinity for DA transporters. The third compound will serve as a backup or will be targeted for other therapeutic indications.



Why develop a new treatment?
   There is great unmet need in the pharmacotherapy of a number of psychiatric disorders due to the low efficacy and side effects of currently used drugs.  According to a landmark study of antidepressant effectiveness conducted by the National Institute of Mental Health known as the Sequenced Treatment Alternatives to Relieve Depression study (STAR*D), only about one-half of subjects taking the initial treatment, a standard antidepressant called citalopram,  either failed to experience significant reduction in their symptoms or were unable to tolerate the side effects.  By the end of the study, even after four different treatment attempts, nearly a third of those subjects still remaining in the study continued to experience significant symptoms, and over half of those subjects initially enrolled had withdrawn from the study without satisfactory treatment response.
   Furthermore, this study did not include those individuals with other commonly associated factors such as severe anxiety, trauma, substance abuse or pain, which in real life may further reduce treatment retention and effectiveness
Why develop another reuptake inhibitor?
   Most treatments in current use are known as reuptake inhibitors, targeting either the serotonin system, or both the serotonin and norepinephrine neurotransmitter systems. Reuptake inhibitors block the rapid clearance of neurotransmitter from the synaptic cleft by transporters and thereby enhance signaling. These compounds enhance the signal only when the neuron fires and thus the action is considered activity dependent. This is a more physiologically sound approach than flooding the synapse with exogenous agonists and furthermore is rate-limited in effect to provide greater safety and tolerability.
Why develop a Triple Reuptake Inhibitor? 

   Many psychiatric disorders are complex in regards to symptoms, pathogenesis and result from a variety of causes including genetic, developmental and situational.  Given the complexity of these disorders, it is unlikely that current Treatments known as dual-reuptake inhibitors targeting both serotonin and norepinephrine (SNRI) such as venlafaxine and duloxetine, have been demonstrated to offer greater effectiveness and improved tolerability for those individuals who do not do well with single reuptake inhibitor pharmacotherapy targeting only the serotonin system (SSRI).  Accordingly, many companies have undertaken the development of a triple-reuptake inhibitor in an effort to further improve treatment effectiveness and tolerability. However, efforts based on those molecular frameworks already in use for existing single- and dual-reuptake inhibitors have encountered unexpected challenges delivering either improvement in effectiveness or tolerability.
   TRImaran Pharma believes its patented technology, based on a novel chemical structure found in many naturally-occurring compounds such as antioxidants, will provide better tolerability than current drugs. These pyran compounds, mechanistically triple reuptake inhibitors (TRIs), can potentially address unmet needs in MDD, PTSD, and ADHD as well as other disorders of mood and behavior associated with significant impairment of normal function.
    As their name implies, these drugs are tri-functional in mechanism. They enhance the neurotransmission of three key neurotransmitters - serotonin (5-HT), norepinephrine (NE), and dopamine(DA) by blocking the clearance of the target neurotransmitter from the synapse by the monoaminergic transporter. 
      
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