CX614

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CX614
CX614.png
CX614 molecule ball.png
Clinical data
Other namesCX-614
Legal status
Legal status
Identifiers
  • 2H,3H,6aH-pyrrolidino(2,1-3',2')1,3-oxazino(6',5'-5,4)benzo(e)1,4-dioxan-10-one
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
Formula C13H13NO4
Molar mass 247.250 g·mol−1
3D model (JSmol)
  • C1CC2N(C1)C(=O)C3=CC4=C(C=C3O2)OCCO4
  • 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]

See also

Related Research Articles

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Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein that, in humans, is encoded by the BDNF gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the canonical nerve growth factor (NGF), a family which also includes NT-3 and NT-4/NT-5. Neurotrophic factors are found in the brain and the periphery. BDNF was first isolated from a pig brain in 1982 by Yves-Alain Barde and Hans Thoenen.

<span class="mw-page-title-main">Ampakine</span> Subgroup of AMPA receptor positive allosteric modulators

Ampakines or AMPAkines are a subgroup of AMPA receptor positive allosteric modulators with a benzamide or closely related chemical structure. They are also known as "CX compounds". Ampakines take their name from the AMPA receptor (AMPAR), a type of ionotropic glutamate receptor with which the ampakines interact and act as positive allosteric modulators (PAMs) of. Although all ampakines are AMPAR PAMs, not all AMPAR PAMs are ampakines.

<span class="mw-page-title-main">CX717</span> Ampakine

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<span class="mw-page-title-main">CX-516</span> Chemical compound

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<span class="mw-page-title-main">Farampator</span> Chemical compound

Farampator is an ampakine drug. It was developed by Cortex Pharmaceuticals, and licensed to Organon BioSciences for commercial development. Following the purchase of Organon by Schering-Plough in 2007, the development license to farampator was transferred. The development of farampator was eventually terminated, reportedly due to concerns about cardiac toxicity.

<span class="mw-page-title-main">CX-546</span> Chemical compound

CX-546 is an ampakine drug developed by Cortex Pharmaceuticals.

<span class="mw-page-title-main">Metabotropic glutamate receptor 1</span> Mammalian protein found in humans

The glutamate receptor, metabotropic 1, also known as GRM1, is a human gene which encodes the metabotropic glutamate receptor 1 (mGluR1) protein.

<span class="mw-page-title-main">Metabotropic glutamate receptor 2</span> Mammalian protein found in humans

Metabotropic glutamate receptor 2 (mGluR2) is a protein that, in humans, is encoded by the GRM2 gene. mGluR2 is a G protein-coupled receptor (GPCR) that couples with the Gi alpha subunit. The receptor functions as an autoreceptor for glutamate, that upon activation, inhibits the emptying of vesicular contents at the presynaptic terminal of glutamatergic neurons.

<span class="mw-page-title-main">Alpha-7 nicotinic receptor</span>

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<span class="mw-page-title-main">IDRA-21</span> Chemical compound

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<span class="mw-page-title-main">LY-503430</span> Chemical compound

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<span class="mw-page-title-main">PEPA (drug)</span> Chemical compound

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<span class="mw-page-title-main">LY-404187</span> Chemical compound

LY-404187 is an AMPA receptor positive allosteric modulator which was developed by Eli Lilly and Company. It is a member of the biarylpropylsulfonamide class of AMPA receptor potentiators.

In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimuli. Some of them, like benzodiazepines or alcoholic beverages, function as psychoactive drugs. The site that an allosteric modulator binds to is not the same one to which an endogenous agonist of the receptor would bind. Modulators and agonists can both be called receptor ligands.

<span class="mw-page-title-main">SKF-83,959</span> Chemical compound

SKF-83,959 is a synthetic benzazepine derivative used in scientific research which acts as an agonist at the D1–D2 dopamine receptor heteromer. It behaves as a full agonist at the D1 protomer and a high-affinity partial agonist at the D2 protomer. It was further shown to act as an allosteric modulator of the sigma-1 receptor. SKF-83,959 additionally inhibits sodium channels as well as delayed rectifier potassium channels. SKF-83,959 is a racemate that consists of the R-(+)- and S-(−)-enantiomers MCL-202 and MCL-201, respectively.

<span class="mw-page-title-main">Pregnenolone sulfate</span> Chemical compound

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<span class="mw-page-title-main">S-18986</span> Chemical compound

S-18986 is a positive allosteric modulator of the AMPA receptor related to cyclothiazide. It has nootropic and neuroprotective effects in animal studies, and induces both production of BDNF and AMPA-mediated release of noradrenaline and acetylcholine in the hippocampus and frontal cortex of the brain.

<span class="mw-page-title-main">ORG-26576</span> Ampakine

ORG-26576 is an ampakine originally developed by Cortex Pharmaceuticals and then licensed to Organon International for development. In animal studies it has been shown to effectively potentiate AMPA receptor function, leading to increased BDNF release and enhanced neuronal differentiation and survival, as well as producing nootropic effects in standardised assays. Development as an antidepressant has been halted due to a failed Phase II trial for major depressive disorder.

<span class="mw-page-title-main">Tulrampator</span> Chemical compound

Tulrampator is a positive allosteric modulator (PAM) of the AMPA receptor (AMPAR), an ionotropic glutamate receptor, which is under development by RespireRx Pharmaceuticals and Servier for the treatment of major depressive disorder, Alzheimer's disease, dementia, and mild cognitive impairment. Tulrampator was in phase II clinical trial for depression, but failed to show superiority over placebo. There are also phase II clinical trials for Alzheimer's disease and phase I trials for dementia and mild cognitive impairment.

<span class="mw-page-title-main">AMPA receptor positive allosteric modulator</span>

AMPA receptor positive allosteric modulators are positive allosteric modulators (PAMs) of the AMPA receptor (AMPR), a type of ionotropic glutamate receptor which mediates most fast synaptic neurotransmission in the central nervous system.

References

  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.
  3. 1 2 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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