CX614: Difference between revisions

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| legal_status = Investigational New Medicine

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| molecular_weight = 247.24662 g/mol

'''CX-614''' is an [[ampakine]] drug developed by Cortex Pharmaceuticals. It has been investigated for its effect on [[AMPA receptor]]s.<ref name="pmid10999951">{{cite journal |author=Arai AC, Kessler M, Rogers G, Lynch G |title=Effects of the potent ampakine CX614 on hippocampal and recombinant AMPA receptors: interactions with cyclothiazide and GYKI 52466 |journal=Mol. Pharmacol. |volume=58 |issue=4 |pages=802–13 |year=2000 |pmid=10999951 |doi=}}</ref>

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]] <ref>{{cite journal |author=Lauterborn JC, Truong GS, Baudry M, Bi X, Lynch G, Gall CM |title=Chronic elevation of brain-derived neurotrophic factor by ampakines |journal=J Pharmacol Exp Ther. |volume=307 |issue=1 |pages=297–305 |year=2003 |month=Oct |pmid=12893840 |doi=10.1124/jpet.103.053694 }}</ref> 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]] <ref name="Jourdi2009">{{cite journal |author=Jourdi H, Hsu YT, Zhou M, Qin Q, Bi X, Baudry M |title=POSITIVE AMPA RECEPTOR MODULATION RAPIDLY STIMULATES BDNF RELEASE AND INCREASES DENDRITIC mRNA TRANSLATION |journal=J Neurosci. |volume=29 |issue=27 |pages=8688–8697 |year=2009 |month=Jul |pmid=19587275 |doi=10.1523/JNEUROSCI.6078-08.2009 |pmc=2761758 }}</ref> 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]].<ref name="Jourdi2009" />

CX-614 has also been proposed as a treatment for conditions such as depression and schizophrenia,<ref>{{cite journal |author=Jin R, Clark S, Weeks AM, Dudman JT, Gouaux E, Partin KM |title=Mechanism of positive allosteric modulators acting on AMPA receptors |journal=J Neurosci. |volume=25 |issue=39 |pages=9027–36 |year=2005 |month=Sep |pmid=16192394 |doi=10.1523/JNEUROSCI.2567-05.2005 }}</ref><ref>{{cite journal |author=Lynch G |title=Glutamate-based therapeutic approaches: ampakines |journal=Curr Opin Pharmacol |volume=6 |issue=1 |pages=82–8 |year=2006 |month=Feb |pmid=16361116 |doi=10.1016/j.coph.2005.09.005 }}</ref> but produces receptor downregulation following chronic administration, which might limit the potential for extended use.<ref>{{cite journal |author=Jourdi H, Lu X, Yanagihara T, ''et al.'' |title=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 |journal=J Pharmacol Exp Ther. |volume=314 |issue=1 |pages=16–26 |year=2005 |month=Jul |pmid=15784649 |pmc=1554891 |doi=10.1124/jpet.105.083873 }}</ref><ref>{{cite journal |author=Mitchell NA, Fleck MW |title=Targeting AMPA Receptor Gating Processes with Allosteric Modulators and Mutations |journal=Biophys J. |volume=92 |issue=7 |pages=2392–402 |year=2007 |month=Apr |pmid=17208968 |pmc=1864835 |doi=10.1529/biophysj.106.095091 }}</ref>

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]]<ref>{{cite journal |title=Ampakines cause sustained increases in BDNF signaling at excitatory synapses without changes in AMPA receptor subunit expression |journal= Neuroscience |volume=159 |issue=1 |pages=283–295 |year=2009 |month=Mar |pmid=19141314 |pmc=2746455 |doi=10.1016/j.neuroscience.2008.12.018 |author=Lauterborn JC, Pineda E, Chen LY, Ramirez EA, Lynch G, Gall CM }}</ref>.

Importantly, such short and intermittent treatment protocols are neuroprotective against neurotoxicity induced with [[MPTP]] and MPP⁺ in cultured midbrain (mesencephalic) and hippocampal organotypic slices.<ref>>{{cite journal |author=Jourdi H, Hamo L, Oka T, Seegan A, Baudry M |title=BDNF mediates the neuroprotective effects of positive AMPA receptor modulators against MPP⁺-induced toxicity in cultured hippocampal and mesencephalic slices |journal=Neuropharmacology |volume=56 |issue=5 |pages=876–885 |year=2009 |month=Apr |pmid=19371576 |doi=10.1016/j.neuropharm.2009.01.015 }}</ref>.

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.<ref>{{cite journal |author=Hess US, Whalen SP, Sandoval LM, Lynch G, Gall CM |title=Ampakines reduce methamphetamine-driven rotation and activate neocortex in a regionally selective fashion |journal=Neuroscience |volume=121 |issue=2 |pages=509–21 |year=2003 |pmid=14522010 |url=http://linkinghub.elsevier.com/retrieve/pii/S0306452203004238 |doi=10.1016/S0306-4522(03)00423-8}}</ref>

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{{Psychostimulants, agents used for ADHD and nootropics}}

{{Glutamate_receptor_ligands}}

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