Nerve cells of the brain and nervous system, called neurons, communicate through chemical messengers called neurotransmitters. The communication between neurons not only enables routine function of the nervous system, but also allows the cells of the nervous system to adapt in response to external stimuli. The main process through which neurons modify their activity in response to stimuli is called synaptic plasticity. The hallmarks of synaptic plasticity include changes in the structure and function of neurons, such as growth of nerve cell endings and strengthening of synaptic connections. These lasting changes in neuronal structure and function translate into changes in learning, memory, cognition, pain perception, mood, and behavior.
NMDA receptors receive signals from certain neurotransmitters (glutamate and glycine) and are critically important in normal brain and nervous system function. The activation and opening of NMDA receptor channels triggers a cascade of events resulting in synaptic plasticity. Driving synaptic plasticity through the modulation of NMDA receptors is a therapeutic approach to treating disorders of the brain and nervous system by enabling appropriate responses to external stimuli which facilitate stabilization of neuropsychiatric function.
NMDA receptors play a critical role in synaptic plasticity and communication among neurons, communication that is vital to learning and memory processes. Abnormalities in synaptic plasticity underlie a number of disorders. Disorders of cognitive ability such as dementia and mild cognitive impairment, or MCI, seen in Alzheimer’s disease, Parkinson’s disease, stroke, traumatic brain injury, and numerous other diseases, clearly indicate an intuitive connection to the process of learning, thinking, and forming memories driven by synaptic plasticity. In many cognitive disorders, people undergo progressive loss of structure or function of neural cells. Here, the disease pathology may trigger an inability to properly attend to stimuli, learn, or remember how to perform tasks driven by a similar lack of synaptic plasticity.
There are a number of additional disorders where a similar lack of effective learning or memory plays a critical role. For example, in PTSD, chronic pain, and depression, there is evidence that specific regions of the brain exhibit a lack of plasticity and the ability to appropriately learn. Therapeutic approaches that modulate NMDA receptors to enhance synaptic plasticity hold great promise for alleviating these disorders, among others.
Given the pivotal role of NMDA receptors in brain and nervous system function and disorders, for decades researchers have attempted to discover and develop compounds that target these receptors. But they have faced significant challenges. Compounds that activate or turn “on” NMDA receptors, called agonists, can produce neuronal damage by over-activating the receptors. As a result, most research on NMDA receptor modulation to date has focused on receptor antagonists, which inhibit or turn “off” NMDA receptor function to achieve efficacy in the treatment of central nervous system diseases. However, there are a number of safety concerns with this approach. By turning off NMDA receptor channel activation, antagonists inhibit the formation of long-term plasticity, the strengthening of nerve cell connections and, ultimately, learning and memory formation. NMDA receptor antagonism can also lead to serious side effects, including psychosis-like symptoms.
Aptinyx has taken a different approach to targeting NMDA receptors, developing compounds that modulate NMDA receptors without ever fully turning them “on” or “off.” In preclinical studies, Aptinyx compounds have demonstrated optimal modulation of NMDA receptors, facilitating receptor activation without over-activating and without the side effects often seen with NMDA receptor antagonists.