Chemistry:CX614
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| Other names | CX-614 |
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| Formula | C13H13NO4 |
| Molar mass | 247.250 g·mol−1 |
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CX-614 is an ampakine drug developed by Cortex Pharmaceuticals. It has been investigated for its effect on AMPA receptors.[1]
Chronic CX-614 treatments produce rapid increases in the synthesis of the brain-derived neurotrophic factor BDNF which has very important effects on synaptic plasticity[2] and may have applications in the treatment of neurodegenerative diseases such as Alzheimer's disease.
Acute CX-614 treatments activate local mRNA translation (new protein synthesis) within dendrites[3] and this is mediated by a fast upregulation of BDNF release. CX-614-dependent release of BDNF rapidly increases translation of proteins that are important for synaptic plasticity such as ARC/Arg3.1 and CaMKIIalpha.[3]
CX-614 has also been proposed as a treatment for conditions such as depression and schizophrenia,[4][5] but produces receptor downregulation following chronic administration, which might limit the potential for extended use.[6][7]
However, downregulation of AMPA receptors with prolonged CX-614 administration can be avoided by designing and using short and intermittent treatment protocols, which could still upregulate BDNF protein levels without reducing the levels of AMPA receptors.[8]
Importantly, such short and intermittent treatment protocols are neuroprotective against neurotoxicity induced with MPTP and MPP+ in cultured midbrain (mesencephalic) and hippocampal organotypic slices.[9]
These results uncovered the neuroprotective effects of CX-614 and indicated that opened the way for further experimentation with CX-614 as an important new treatment for Parkinson's disease and Alzheimer's disease.
CX-614 has also been shown to reduce the behavioural effects of methamphetamine in mice, and may have application in the treatment of stimulant abuse.[10]
See also
References
- ↑ "Effects of the potent ampakine CX614 on hippocampal and recombinant AMPA receptors: interactions with cyclothiazide and GYKI 52466". Mol. Pharmacol. 58 (4): 802–13. 2000. doi:10.1124/mol.58.4.802. PMID 10999951.
- ↑ "Chronic elevation of brain-derived neurotrophic factor by ampakines". J Pharmacol Exp Ther 307 (1): 297–305. Oct 2003. doi:10.1124/jpet.103.053694. PMID 12893840.
- ↑ 3.0 3.1 "POSITIVE AMPA RECEPTOR MODULATION RAPIDLY STIMULATES BDNF RELEASE AND INCREASES DENDRITIC mRNA TRANSLATION". J. Neurosci. 29 (27): 8688–8697. Jul 2009. doi:10.1523/JNEUROSCI.6078-08.2009. PMID 19587275.
- ↑ "Mechanism of positive allosteric modulators acting on AMPA receptors". J. Neurosci. 25 (39): 9027–36. Sep 2005. doi:10.1523/JNEUROSCI.2567-05.2005. PMID 16192394.
- ↑ Lynch G (Feb 2006). "Glutamate-based therapeutic approaches: ampakines". Curr Opin Pharmacol 6 (1): 82–8. doi:10.1016/j.coph.2005.09.005. PMID 16361116.
- ↑ "Prolonged Positive Modulation of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors Induces Calpain-Mediated PSD-95/Dlg/ZO-1 Protein Degradation and AMPA Receptor Down-Regulation in Cultured Hippocampal Slices". J Pharmacol Exp Ther 314 (1): 16–26. Jul 2005. doi:10.1124/jpet.105.083873. PMID 15784649.
- ↑ "Targeting AMPA Receptor Gating Processes with Allosteric Modulators and Mutations". Biophys. J. 92 (7): 2392–402. Apr 2007. doi:10.1529/biophysj.106.095091. PMID 17208968. Bibcode: 2007BpJ....92.2392M.
- ↑ "Ampakines cause sustained increases in BDNF signaling at excitatory synapses without changes in AMPA receptor subunit expression". Neuroscience 159 (1): 283–295. Mar 2009. doi:10.1016/j.neuroscience.2008.12.018. PMID 19141314.
- ↑ "BDNF mediates the neuroprotective effects of positive AMPA receptor modulators against MPP+-induced toxicity in cultured hippocampal and mesencephalic slices". Neuropharmacology 56 (5): 876–885. Apr 2009. doi:10.1016/j.neuropharm.2009.01.015. PMID 19371576.
- ↑ "Ampakines reduce methamphetamine-driven rotation and activate neocortex in a regionally selective fashion". Neuroscience 121 (2): 509–21. 2003. doi:10.1016/S0306-4522(03)00423-8. PMID 14522010.
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