Science

Our compounds work through modulation of the NMDA receptor – a key regulator of communication among cells of the the brain and nervous system.

Nerve Cell Communication: The Role of Synaptic Plasticity and the NMDA Receptor

Nerve cells of the brain and nervous system communicate through chemical messengers called neurotransmitters. The communication between nerve cells 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 nerve cells modify their activity in response to stimuli is called synaptic plasticity. The hallmarks of synaptic plasticity include changes in the structure and function of nerve cells, such as growth of nerve cell endings and strengthening of synaptic connections. These lasting changes in nerve cell structure and function translate into changes in learning, memory, cognition, pain perception, and behavior.

The NMDA receptor receives signals from certain neurotransmitters (glutamate and glycine) and is 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.

brain-connectivity

The Role of the NMDA Receptor in Brain and Nervous System Disease

The NMDA receptor plays a critical role in synaptic plasticity and communication among nerve cells. As such, function of the NMDA receptor has been linked to multiple diseases of the brain and central nervous system such as depression, schizophrenia, attention deficit hyperactivity disorder and autism. Hyper- or hypo- excitability of the NMDA receptor may result in neurodegenerative processes associated with diseases such as neuropathic pain, stroke, dementia, and Alzheimer’s. In addition, targeting the NMDA receptor can be a symptomatic approach to treating diseases involving symptoms such as cognitive impairment.

NMDA Receptor-Targeted Therapeutics: The Delicate Balance between Toxicity and Efficacy

Given the pivotal role of the NMDA receptor in brain and nervous system function and disorders, for decades researchers have attempted to discover and develop compounds that target this receptor. But they have faced significant challenges. Compounds that activate or turn “on” the NMDA receptor, called agonists, can produce neuronal damage by over-activating the receptor. 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. Antagonists turn off NMDA receptor channel activation completely, inhibiting the formation of long-term plasticity, the strengthening of nerve cell connections and, ultimately, learning and memory formation. NMDA receptor antagonism can also leads to serious side effects, including psychosis-like symptoms.

Aptinyx has taken a different approach to targeting the NMDA receptor, developing compounds that modulate the NMDA receptor without ever fully turning it “on” or “off.” In preclinical studies, our compounds have demonstrated optimal modulation of the NMDA receptor, facilitating receptor activation without over-activating the receptor and without causing the side effects seen with NMDA receptor antagonists.