Technology
AMPAKINE compounds facilitate the activity of the AMPA receptor, which are activated by the neurotransmitter glutamate, the most prominent excitatory neurotransmitter in the human brain. The AMPAKINE compounds interact in a highly specific manner with the AMPA receptor, lowering the amount of neurotransmitter required to generate a response, and increasing the magnitude and/or duration of the response to any given amount of glutamate. Cortex believes that this selective amplification of the normal glutamate signal may eventually lead to utility in the treatment of neurological diseases and disorders characterized by depressed functioning of the glutamatergic pathways in the brain.
Cortex’s AMPAKINE technology is composed of two groups of compounds that are designated as “low impact” and “high impact”.
AMPAKINE compounds like CX614 and CX929 bind to the well characterized cyclothiazide binding site, and are referred to as high impact compounds. In contrast, compounds like CX717, CX701, Org24448 and Org26576 bind to a different modulatory site on the AMPA receptor complex and impact the response in unique ways. Both types of compounds positively modulate the AMPA receptor function; low impact compounds increase the amplitude of the neuronal action potential, while the high impact compounds generally increase both the amplitude and the half-width of the neuronal action potential. Additionally, the high impact compounds activate the expression of certain genes in the neuron, including neurotrophins such as Brain Derived Neurotrophic Factor (“BDNF”). BDNF mediates the differentiation and survival of neurons by providing the necessary trophic support, and modulates synaptic transmission and plasticity. We believe that this action of AMPAKINE molecules imparts these compounds with the potential for disease modifying activity, since deficits in BDNF have been observed in psychiatric disorders, such as; anxiety, depression, and ADHD, and neurodegenerative disease such as Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and Fragile X.
Although low impact AMPAKINE compounds do not significantly enhance neurotrophic factors, they are able to improve the strength of the synaptic connections through their potentiation of the AMPA receptors.
Drug-induced respiratory depression is a life-threatening condition caused by analgesic, hypnotic, and anesthesia medications. Respiratory depression may arise during physician-supervised procedures such as surgical anesthesia, post-operative analgesia, and as a result of normal out-patient management of pain from surgery, cancer, accidents, or illnesses. The most common treatment of opiate-induced respiratory depression is to administer opiate receptor antagonists, drugs that block the effectiveness of opiate analgesia. While this approach may prevent a serious side effect or even death, it dramatically reduces the effectiveness of drugs administered for management of severe pain.
The AMPAKINE molecule CX717, and other AMPAKINE compounds, have been studied in several animal species in opiate- and barbiturate-induced respiratory depression to understand their potential to counter respiratory depression while simultaneously allowing the sedative or analgesic to continue working as it was intended.
Through stimulation of neurons located in the pre-Bötzinger complex located in the brain stem, AMPAKINE compounds appear to prevent or rapidly reverse respiratory depression induced by opiates and barbiturates (central nervous system depressants) without inhibition of their respective analgesic and sedative effects.
In the February 2008 issue of Neuropathology, the article by Lavezzi et al is the first published article (reference listed below) confirming the presence of the pre-Bötzinger Complex (PBC) in man. It appears that the PBC in humans is located in the medulla oblongata, the same region of the brain stem that has been identified by Drs. Jack Feldman’s group at UCLA and Dr. John Greer’s group at U. Alberta in rats and in other animal species.
The mechanism by which AMPAKINE compounds work apparently is due to enhancing glutamatergic drive by turning on the large numbers of AMPA receptors specifically found in the PBC in the different animal species tested to date. Both lines of research enhance Cortex's optimism about demonstrating for the first time in human subjects that acute oral dosing of AMPAKINE CX717 will prevent opiate (alalfentanil) induced respiratory depression in two Phase II double blinded studies being conducted in human subjects in Europe. The Company anticipates that the first study should have top-line data in late June - early July with the other study reporting shortly thereafter. Cortex is currently working on an I.V. formulation for CX717 for use in additional human studies.
References:
J. Ren, B. Y. Poon, Y. Tang, G. D. Funk, and J. J. Greer - Ampakines Alleviate Respiratory Depression in Rats - Am J Respir Crit Care Med, 2006; 174:1384–1391
J L. Feldman and C A. Del Negr. Looking for inspiration: new perspectives on respiratory rhythm: Nat Rev Neurosci. 2006; 7(3): 232-42.
A. M. Lavezzi and L. Matturri; Functional neuroanatomy of the human pre-Bötzinger complex with particular reference to sudden unexplained perinatal and infant death: Neuropathology 2008;28: 10-16
Y. Tsuboi, D.W. Dickson, K. Nabeshima, A.M. Schmeichel, Z.K. Wszolek, T. Yamada, E.E. Benarroch. Neurodegeneration involving putative respiratory neurons in Perry syndrome. Acta Neuropathol. 2008;115(2):263-8
E.E. Benarroch. Brainstem respiratory control: substrates of respiratory failure of multiple system atrophy. Mov Disord. 2007; 22(2): 155-61