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Pharmacology BQ-869, Novel NMDA Antagonist.

This thread contains discussion about a Pharmacology-related topic
MedicinalUser247

MedicinalUser247

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BQ-869 is a powerful NMDA Antagonist. Even stronger than MK-801. Right now it's being studied to be useful for Stroke and Brain Damage and who knows what else it could be good for. I did a little reading on it and thought it would be a good topic to talk about in the Neuroscience and Pharmacology section. I want to ask a Scientist in this Forum if they've ever worked with BQ-869 and if it has the same reaction to the body as MK-801 does or if BQ-869 is less Psychotic producing than MK-801. The other question is has there already been any Human Trials of it yet ? If yes what are the findings ?
 
Do you know if there are any recent studies on it? The most recent I could find was in 2015 and 2020
 
MedicinalUser247 said:
BQ-869 is a powerful NMDA Antagonist. Even stronger than MK-801. Right now it's being studied to be useful for Stroke and Brain Damage and who knows what else it could be good for. I did a little reading on it and thought it would be a good topic to talk about in the Neuroscience and Pharmacology section. I want to ask a Scientist in this Forum if they've ever worked with BQ-869 and if it has the same reaction to the body as MK-801 does or if BQ-869 is less Psychotic producing than MK-801. The other question is has there already been any Human Trials of it yet ? If yes what are the findings ?
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First of all, are there carcinogenicity/mutagenicity studies? As a derivative of aminophenanthrene, BQ-869 is likely to be carcinogenic.
 
Didgital said:
neat structure, could def get a chloro and ketone on there
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Two chiral centres only one isomer is active. So it ends up not being quite as useful as one might think. If memory serves the (S)-trans is the one but it's an awfully long walk to find out that most people actually like compounds that are NMDA angagonists AND DRIs. Certainly the few reports on MK-801 are not every encouraging. After all, the research was to discover compounds that modelled schizophrania, not RCs.
 
I couldn't find any synthesis data for BQ-869.

However i managed to piece together the following patents: CN103242128 (Ex-5) and WO2011116866.

I was thinking about it some more and came across a compound that is called benzo[def]carbazole. This modified for incorporation of the amine say by the process of oxidation would give a keto-enol tautomer which would give an enamine upon reaction with the methylamine. The chlorine atom could be introduced say by nitration followed by Sandmeyer reaction. However one draw back is the olefin connected to the carbazole ring is conjugated into a phenanthracene ring and therefore has the full aromaticity which means it doesn't behave as an olefin anymore.

I found this though: The oxidation of phenanthrene targets its highly reactive 9,10-positions. Common oxidizing agents (e.g., chromic acid or hydrogen peroxide) convert it into phenanthrene-9,10-quinone. Further oxidation cleaves the central ring, yielding diphenic acid (2,2'-diphenic acid). [1, 2, 3, 4, 5]

It may be necessary to use an acetyl protecting group on the nitrogen prior to performing this step.

However, I checked again and discovered that 4,5-epiminophenanthrene is a carcinogenic component of cigarette smoke and is not commercially available in an quantity.

I was thinking 3-Chlorophenanthrene [715-51-5] might possibly be one of the starting materials.

or N-methylphenanthren-9-amine is in the database also.
 
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I have noted the last splash research into many new ligands is for their potential neuroprotective effects. If you search, EVERYTHING is tested for neuroprotective effect as a last throw of the dice.

At the end of the day, isophenidine is ONE quantitative step with one isomer being an NMDA antagonist, the other a DRI. That is what made that 1,2-diarylethylamine scaffold so interesting. It allows one to tune the NMDA/DRI ratio.

Why isopropyl?


NIPPCA is the most active N-monosubstituted PCP homologue. Obviously ethyl was tested first but the idiots had bought a TONNE of piperidine so made up excuses of why they couldn't synthesize isophenidine even after warnings about MXP. Still, it got them sacked.
 
I found MK-801 antidotes that are being touted as novel solutions to schizophrenia not targeting to dopamine receptor.

Cieślik P, Radulska A, Pelikant-Małecka I, Płoska A, Kalinowski L, Wierońska JM. Reversal of MK-801-Induced Disruptions in Social Interactions and Working Memory with Simultaneous Administration of LY487379 and VU152100 in Mice. Int J Mol Sci. 2019 Jun 6;20(11):2781. doi: 10.3390/ijms20112781. PMID: 31174329; PMCID: PMC6600181.
 
Yeah - Eli Lilly got LY2140023 an indirect NMDA modulator into stage 2 trials as an antipsychotic medication.

Elsewhere I have mentioned that people with schizoprenia were discovered to have increased DOPAC and/or reduced NMDA in their cerebrospinal fluid. But those who ONLY lack NMDA make up about 10% of sufferers. So not a suprise that for those it helped, it was great, but if your medication could only be appropriate in 10% of cases, it's not going to be a blockbuster.

I think it's been held-off being an orphan drug in the hope that medicine catches up i.e. personalized medicine. I doubt it.
 
I think the big blockbuster they are working on for an antipsychotic that does not affect dopamine is called ulotaront. However, this has nothing to do with NMDA receptors so might appear off-topic in this thread.

Spoelstra SK, Bruggeman R, Knegtering H. Een antipsychoticum zonder dopaminereceptorblokkade? [An antipsychotic without dopamine receptor blockade?]. Tijdschr Psychiatr. 2021;63(11):804-809. Dutch. PMID: 34851520.

I'm interested in the cholingeric theory of schizophrenia since the majority of schizophrenics are addicted to nicotine and it supplies relief to their symptoms.

I came across a drug recently developed called Cobenfy that is only available in the USA at this time point.

If you read the patents to drugs like sazetidine-A (saz-A) and more recently, VMY-2-95, you can see that schizophrenia is one of the indications for which the medicine could be useful (although there is a long list or applications).
 
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I see Ulataront turned out to be no better than a placebo. Then the classic 'let's see if it does SOMETHING we can sell' which always seems to end badly. Whenever you see a candidate being sold off to smaller and smaller companies, likely it's researchers reading the side-effects. As if an antipsychotic is an appropriate hypnotic FFS.

Cobenfy looks a lot like drug 2 included to offset side-effects of drug 1. The problem with a fixed dose is just that. you cannot optimize the doses of each to the patient. I noted oxycodone + low-dose nalmefene failed because so many people in the study dropped out. I suggest the problem with a new antipsychotic is that often the patient isn't in control of consent i.e. patients cannot drop out - which is a bit cruel (but the whole industry is amoral so I shouldn't be surprised).


Now this is interesting - read about the two psychartists. Both are PAYED by Eli Lilly yet I see no conflict-of-interest declarations.

I also noted a few odd terms such as antipsychotic-like repeated everywhere. The clue is in the word ANTI psychotic. So what on earth does antipsychotic-like MEAN? That violent patients are zoned out? Also suggesting on one hand it doesn't produce sedation and in the same sentence say it produces sleepiness?

If it truly helps people, I'm all for it but I have studied so-called 'blockbusters' come and go. COX-2 inhibitors being the classic. Actually really good for short-term use but the way the makers simply withdrew most from the market JUST before the stage 4 trials (yep - pharmacovigilance has a new name so every medication is ALWAYS on trial) came out shows that profit is king.

As far as I can work out they have move upstream somewhat as the action of M1 and M1 ligands was known.

I thank you for alerting me to this new medication - I don't know if it IS a blockbuster as even those in the pay of the makers admit it required 'the right patient' but it could be an interesting thing to build on.
 
If you're interested in a related drug, please take the time to checck out an earlier revision on the vedaclidine document.

en.wikipedia.org

Vedaclidine - Wikipedia

en.wikipedia.org en.wikipedia.org

You can see there is actually a patent attached for use in schizophrenia:

Franklin Porter Bymaster, et al. WO1995005379 (Novo Nordisk AS).
 
Yeah that's an old one but xanomeline itself is a really old patent and they still managed to give it a recent brand name (Cobenfy).

Per Sauerberg & Preben H. Olesen, US5712297 (1998 to Novo Nordisk AS).
Mirza, N. R., Peters, D., Sparks, R. G. (June 2003). "Xanomeline and the Antipsychotic Potential of Muscarinic Receptor Subtype Selective Agonists". CNS Drug Reviews. 9 (2): 159–186. doi:10.1111/j.1527-3458.2003.tb00247.x.
Bender, A. M., Jones, C. K., Lindsley, C. W. (15 March 2017). "Classics in Chemical Neuroscience: Xanomeline". ACS Chemical Neuroscience. 8 (3): 435–443. doi:10.1021/acschemneuro.7b00001.

If you are really interested in the cholinergic theory of schizophrenia you should see some of the alpha7 nicotinic agonists that are being developed.

It's not like it is only useful in treating schizophrenia, but you would need to have some kind of a diagnosis to get prescribed a medicine.
 
Well, again, that patent has expired. I would expect that the mixture has been patented somewhere. Otherwise nothing to stop a competitor simply producing a generic.
 
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