CX614

CX614
Clinical data
Other names	CX-614
Legal status
Legal status	US: Investigational New Drug;
Identifiers
	IUPAC name 2H,3H,6aH-pyrrolidino(2,1-3',2')1,3-oxazino(6',5'-5,4)benzo(e)1,4-dioxan-10-one;
CAS Number	191744-13-5 ;
PubChem CID	6451148;
IUPHAR/BPS	7842;
ChemSpider	4953628;
UNII	87V631480W;
CompTox Dashboard (EPA)	DTXSID30912324 ;
Chemical and physical data
Formula	C13H13NO4
Molar mass	247.250 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES C1CC2N(C1)C(=O)C3=CC4=C(C=C3O2)OCCO4;
	InChI InChI=1S/C13H13NO4/c15-13-8-6-10-11(17-5-4-16-10)7-9(8)18-12-2-1-3-14(12)13/h6-7,12H,1-5H2; Key:RQEPVMAYUINZRE-UHFFFAOYSA-N;
	(verify)

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]

References

^ Arai AC, Kessler M, Rogers G, Lynch G (2000). "Effects of the potent ampakine CX614 on hippocampal and recombinant AMPA receptors: interactions with cyclothiazide and GYKI 52466". Mol. Pharmacol. 58 (4): 802–13. doi:10.1124/mol.58.4.802. PMID 10999951. S2CID 6489143.
^ Lauterborn JC, Truong GS, Baudry M, Bi X, Lynch G, Gall CM (Oct 2003). "Chronic elevation of brain-derived neurotrophic factor by ampakines". J Pharmacol Exp Ther. 307 (1): 297–305. doi:10.1124/jpet.103.053694. PMID 12893840. S2CID 1235935.
^ ^a ^b Jourdi H, Hsu YT, Zhou M, Qin Q, Bi X, Baudry M (Jul 2009). "POSITIVE AMPA RECEPTOR MODULATION RAPIDLY STIMULATES BDNF RELEASE AND INCREASES DENDRITIC mRNA TRANSLATION". J. Neurosci. 29 (27): 8688–8697. doi:10.1523/JNEUROSCI.6078-08.2009. PMC 2761758. PMID 19587275.
^ Jin R, Clark S, Weeks AM, Dudman JT, Gouaux E, Partin KM (Sep 2005). "Mechanism of positive allosteric modulators acting on AMPA receptors". J. Neurosci. 25 (39): 9027–36. doi:10.1523/JNEUROSCI.2567-05.2005. PMC 6725607. 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.
^ Jourdi H, Lu X, Yanagihara T, et al. (Jul 2005). "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. doi:10.1124/jpet.105.083873. PMC 1554891. PMID 15784649.
^ Mitchell NA, Fleck MW (Apr 2007). "Targeting AMPA Receptor Gating Processes with Allosteric Modulators and Mutations". Biophys. J. 92 (7): 2392–402. Bibcode:2007BpJ....92.2392M. doi:10.1529/biophysj.106.095091. PMC 1864835. PMID 17208968.
^ Lauterborn JC, Pineda E, Chen LY, Ramirez EA, Lynch G, Gall CM (Mar 2009). "Ampakines cause sustained increases in BDNF signaling at excitatory synapses without changes in AMPA receptor subunit expression". Neuroscience. 159 (1): 283–295. doi:10.1016/j.neuroscience.2008.12.018. PMC 2746455. PMID 19141314.
^ Jourdi H, Hamo L, Oka T, Seegan A, Baudry M (Apr 2009). "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. doi:10.1016/j.neuropharm.2009.01.015. PMC 3659791. PMID 19371576.
^ Hess US, Whalen SP, Sandoval LM, Lynch G, Gall CM (2003). "Ampakines reduce methamphetamine-driven rotation and activate neocortex in a regionally selective fashion". Neuroscience. 121 (2): 509–21. doi:10.1016/S0306-4522(03)00423-8. PMID 14522010. S2CID 23287000.

[pmid10999951-1] Arai AC, Kessler M, Rogers G, Lynch G (2000). "Effects of the potent ampakine CX614 on hippocampal and recombinant AMPA receptors: interactions with cyclothiazide and GYKI 52466". Mol. Pharmacol. 58 (4): 802–13. doi:10.1124/mol.58.4.802. PMID 10999951. S2CID 6489143.

[2] Lauterborn JC, Truong GS, Baudry M, Bi X, Lynch G, Gall CM (Oct 2003). "Chronic elevation of brain-derived neurotrophic factor by ampakines". J Pharmacol Exp Ther. 307 (1): 297–305. doi:10.1124/jpet.103.053694. PMID 12893840. S2CID 1235935.

[Jourdi2009-3] Jourdi H, Hsu YT, Zhou M, Qin Q, Bi X, Baudry M (Jul 2009). "POSITIVE AMPA RECEPTOR MODULATION RAPIDLY STIMULATES BDNF RELEASE AND INCREASES DENDRITIC mRNA TRANSLATION". J. Neurosci. 29 (27): 8688–8697. doi:10.1523/JNEUROSCI.6078-08.2009. PMC 2761758. PMID 19587275.

[4] Jin R, Clark S, Weeks AM, Dudman JT, Gouaux E, Partin KM (Sep 2005). "Mechanism of positive allosteric modulators acting on AMPA receptors". J. Neurosci. 25 (39): 9027–36. doi:10.1523/JNEUROSCI.2567-05.2005. PMC 6725607. PMID 16192394.

[5] 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.

[6] Jourdi H, Lu X, Yanagihara T, et al. (Jul 2005). "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. doi:10.1124/jpet.105.083873. PMC 1554891. PMID 15784649.

[7] Mitchell NA, Fleck MW (Apr 2007). "Targeting AMPA Receptor Gating Processes with Allosteric Modulators and Mutations". Biophys. J. 92 (7): 2392–402. Bibcode:2007BpJ....92.2392M. doi:10.1529/biophysj.106.095091. PMC 1864835. PMID 17208968.

[8] Lauterborn JC, Pineda E, Chen LY, Ramirez EA, Lynch G, Gall CM (Mar 2009). "Ampakines cause sustained increases in BDNF signaling at excitatory synapses without changes in AMPA receptor subunit expression". Neuroscience. 159 (1): 283–295. doi:10.1016/j.neuroscience.2008.12.018. PMC 2746455. PMID 19141314.

[9] Jourdi H, Hamo L, Oka T, Seegan A, Baudry M (Apr 2009). "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. doi:10.1016/j.neuropharm.2009.01.015. PMC 3659791. PMID 19371576.

[10] Hess US, Whalen SP, Sandoval LM, Lynch G, Gall CM (2003). "Ampakines reduce methamphetamine-driven rotation and activate neocortex in a regionally selective fashion". Neuroscience. 121 (2): 509–21. doi:10.1016/S0306-4522(03)00423-8. PMID 14522010. S2CID 23287000.

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CX614

See also

References