Since its formation in 1987, the Company has been engaged in the research and clinical development of ampakines. Ampakines are PAMs of the AMPA glutamate receptor (See illustration). They enhance the excitatory actions of the neurotransmitter glutamate at the AMPA receptor complex, which mediates most excitatory transmission in the CNS (central nervous system). We currently are developing two lead clinical compounds, CX717 and CX1739, and one pre-clinical compound, CX1942. These compounds belong to a new class of ampakines that do not display the electrophysiological and biochemical effects that led to undesirable side effects, namely convulsive activities, previously reported in animal models of earlier generations of such compounds. Thus, our compounds can be viewed as being kinder or gentler than the earlier generations.
In a series of elegant pre-clinical studies, scientists at the University of Alberta, demonstrated that certain brain stem neurons, which regulated breathing, contained within their membranes both AMPA and opioid receptors. Activation of the opiate receptors by opioid drugs reduced the firing of these neurons and depressed breathing. Using ampakines as positive allosteric modulators of the AMPA receptors, the neuronal depressant effects of the opioids was antagonized and breathing was restored. This is not how Narcan® works. Narcan® displaces the opioid at the opioid receptor. Ampakines overcome the respiratory depressive effects of the opioids while leaving the opioids in place, potentially allowing for better pain management.
Through an extensive translational research effort from the cellular level through Phase 2 clinical trials, CX717 and CX1739 were efficacious in treating drug induced respiratory depression caused by opioids without altering the analgesic effects of the opioids. The results of our preclinical research studies have been replicated in three separate Phase 2A human clinical trials with two ampakines CX717 and CX1739, confirming the translational mechanism and target site engagement and demonstrating proof of principle that ampakines act as PAMs of AMPA receptors in humans.