4 replies to this topic

[Reformed-Redan]

S-18986 is an ampakine drug 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 acetylcholinein the hippocampus and frontal cortex of the brain.^{[1][2][3][4][5][6][7][8][9][10]}

[Jeoshua]

Thank you for the Wiki-dump. I've seen that page before and it looks like an interesting compound.

This substance looks very similar in structure and effect to IDRA-21. Are there any studies that have been done comparing the effectiveness of the two?

I think the answer to the question, "why not?", would be that it's so very similar to another compound known to be somewhat... difficult... and looks by its structure to be a lot harder to synthesize than IDRA-21 and likely would fall into the same problem as Unifiram vs Sunifiram, the one being much harder to synthesize than its lesser effective but much more affordable cousin.

 

Found one:
 

S18986: a positive modulator of AMPA receptors enhances (S)-AMPA-mediated BDNF mRNA and protein expression in rat primary cortical neuronal cultures.

The present study describes the effect of (S)-2,3-dihydro-[3,4]cyclopentano-1,2,4-benzothiadiazine-1,1-dioxide (S18986), a positive allosteric modulator of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors, on (S)-AMPA-mediated increases in brain-derived neurotrophic factor (BDNF) mRNA and protein expression in rat primary cortical neuronal cultures. (S)-AMPA (0.01-300 microM) induced a concentration-dependent increase in BDNF mRNA and protein expression (EC(50)=7 microM) with maximal increases (50-fold) compared to untreated cultures observed between 5 and 12 h, whereas for cellular protein levels, maximal expression was detected at 24 h. S18986 alone (< or =300 microM) failed to increase basal BDNF expression. However, S18986 (300 microM) in the presence of increasing concentrations of (S)-AMPA maximally enhanced AMPA-induced expression of BDNF mRNA and protein levels (3-5-fold). S18986 (100-300 microM) potentiated BDNF mRNA induced by 3 microM (S)-AMPA (2-3-fold). Under similar conditions, the AMPA allosteric modulator cyclothiazide induced a potent stimulation of (S)-AMPA-mediated BDNF expression (40-fold; EC(50)=18 microM), whereas IDRA-21 was inactive. Kinetic studies indicated that S18986 (300 microM) in the presence of 3 micro M (S)-AMPA was capable of enhancing BDNF mRNA levels for up to 25 h, compared to 3 microM (S)-AMPA alone. On the other hand, S18986 only partially enhanced kainate-mediated expression of BDNF mRNA, but failed to significantly enhance N-methyl-D-aspartate stimulated BDNF expression levels. In support of these observations, the competitive AMPA receptor antagonist NBQX (1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide) but not the selective NMDA-receptor antagonist, (+)-MK-801 [(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine], abrogated S18986-induced effects on BDNF expression. S18986-mediated enhancement of (S)-AMPA-evoked BDNF protein expression was markedly attenuated in Ca(2+)-free culture conditions. Furthermore, from a series of kinase inhibitors only the Calmodulin-Kinase II/IV inhibitor (KN-62, 25 microM) significantly inhibited (-85%, P<0.001) AMPA+S18986 stimulated expression of BDNF mRNA. The present study supports the observations that AMPA receptor allosteric modulators can enhance the expression of BDNF mRNA and protein expression via the AMPA receptor in cultured primary neurones. Consequently, the long-term elevation of endogenous BDNF expression by pharmacological intervention with this class of compounds represents a potentially promising therapeutic approach for behavioural disorders implicating cognitive deficits.
Affiliation
Servier Research Institute, Division of Molecular Pharmacology and Pathophysiology, 125, Chemin de ronde, 78290 Croissy-sur-Seine, France. brian.lockhart@fr.netgrs.com

Looks like S 18986 is kind of like IDRA-21 with added effect on BDNF. Haven't yet found anything comparing their relative strength as an ampakine yet.

Edited by Jeoshua, 26 April 2014 - 06:05 PM.

[Metagene]

Have a look

 

http://strathprints....rints027822.pdf

http://books.google....21 Ec2x&f=false

 

Perhaps the most advanced member of this 

class is the Servier compound 14 (S-18986), which exhibited an EC2x of 60 μM46 in the current induced 

by AMPA when added to Xenopus oocytes. The Servier group demonstrated that only the (S)-

enantiomer was effective as an AMPA positive allosteric modulator. In spite of its relatively lower 

potency compared to 13, compound 14 is able to penetrate the blood-brain barrier, thus enabling in 

vivo investigation.47 In vivo pharmacological studies using the object recognition test in rat showed that 

14 when dosed from 0.3 to 3 mg/kg p.o. improved the retention of memory and at the 0.3 mg/kg dose 

counteracted the effect of age-related memory deficits.48 

Subsequent studies have shown that analogues derived from 14 have been shown to have superior 

levels of potency (e.g. 15 EC2x = 8.8 μM).45 It remains to be seen if this enhanced potency leads to 

improved in vivo efficacy in, for example, cognition models.

 

[Charles Lee Ray]

The S18986 S enantiomer has an EC2x of 24.6 (30 in the original article) plus or minus 2.9. and an EC5x of 78.2 plus or minus 8.9. The data being cited above (EC2x = 60) is for racemic S18986. Maximum current increase of 1.263%

 

IDRA-21 EC2x is 134 and EC5x 509. MAximum current increase above 700% (does not further specify)

 

EC2x and EC5x are micromolar concentrations of the compound to produce a the 2-fold and 5-fold increase in currents with respect to those produced by 10 micromolar of AMPA. 

 

While the data bears some interest, it does not say much about the "in vivo" effects. The above data comes from rat AMPA receptors in an X laevis oocyte by voltage clamp. So it may or may not be representative of a synapse or an actual neural network. Some of the ridiculously potent AMPA PAM have an EC2x of 0,0007 and about a 4.000% increase in current. However, the big molecules do not cross the blood brain barrier, may have little bioavailability, etc. 

 

Plus, they you have the GluA1-4 subunit selectivity, the flip/flop isoform... they have different distribution in the CNS so some may be good at one thing even though they are not as potent. 

 

S-18986 has evolved from IDRA-21 if I am not mistaken. It has plenty of behavioral enhancing data behind it. Not marvelous but it does have back-up. Not sure about IDRA-21. 

 

Anyway, I have to read more on IDRA-21 but I would say S18 is better... although I may be wrong. 

[Charles Lee Ray]

Oh, and the brain derived neurotrophic factor is really cool stuff. Most ampakines increase the activity dependent local translation of BDNF. BDNF then goes one to do a lot of convenient things.

 

That is good for two reasons.

 

First, BDNF triggers anti-apoptotic, pro-survival and growth intracellular cascades. Ampakines have been shown to protect against excitotoxicity... it seems paradoxical but it makes sense once you read into it.

 

Second, ampakines do it in an activity dependent manner. This means BDNF is up-regulated where it needs to be up-regulated. Increasing BDNF levels everywhere or not being careful with TrkB agonist can lead to a non-computationally sounds enhancement of LTP. Neural networks use synaptic plasticity to make synapses stronger but also weaker. It's a gain mechanism to increase the difference in strength of inputs. So making all synapses strong is not computationally sound (e.g. epilepsy).

 

A good example I recall is CaMKII-alpha. After learning I don't remember what, over-activity of strongly LTP promoting CaMKII was induced. Hypothetically, this was because indiscriminate early-LTP erased the computationally sound LTP. Too much BDNF is not good either.

 

Once I can post references, I'll support the aforementioned.