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Bromide pharmacology

M

Memantine

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May 16, 2015
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How does it cause CNS depression? Is it because of hyperchloremia? Or suppression of the thyroid?

How toxic is bromide?
 
The GABA-A receptor, which is the molecular target of benzos, barbiturates and ethanol, is a chloride ion channel. Bromide, being a halide ion like chloride, will probably somehow affect the functioning of those ion channels. I have tried potassium bromide once at a a dose of about 1 gram, but that was not enough to cause any significant subjective effects. I don't think it will be particularly recreational/euphoric at any dose. Bromide toxicity usually happens if you use bromide medications daily for an extended period of time and there is an accumulation of bromide in your body.'

Here's an old article about the effect of bromide on the electrophysiological ion currents through GABA-A receptor. http://www.ncbi.nlm.nih.gov/pubmed/7843172
 
I was just looking into this just the day before last, interestingly. I was curious as to why a lot of DRI ligands use di-chloro substitutions when they're being optimized but not di-bromo, when the mono-bromide substitution in either meta or para is the only one with better affinity than the mono-chloro in either position. My thoughts were either that it was due to toxicity, which seems unlikely, or that since bromide is a bigger heteroatom that perhaps the bonds terminating in bromide, when adjacent, are splayed at slightly more obtuse angles from one another that might interfere with optimum placement.
 
polymath said:
The GABA-A receptor, which is the molecular target of benzos, barbiturates and ethanol, is a chloride ion channel. Bromide, being a halide ion like chloride, will probably somehow affect the functioning of those ion channels. I have tried potassium bromide once at a a dose of about 1 gram, but that was not enough to cause any significant subjective effects. I don't think it will be particularly recreational/euphoric at any dose. Bromide toxicity usually happens if you use bromide medications daily for an extended period of time and there is an accumulation of bromide in your body.'

Here's an old article about the effect of bromide on the electrophysiological ion currents through GABA-A receptor. http://www.ncbi.nlm.nih.gov/pubmed/7843172
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GABA-A channels are more permeable to bromide ions compared with chloride ions. So GABA-A receptor-induced hyperpolarization is enhanced in the presence of extracellular bromide.
 
geminal dihalogen esp with higher halogens (Br, I) are easily hydrolyzed to a carbonyl (and two halide ions), idk if this is the case why they dont use it.
(geminal means 2 halogens attaching to same carbon; aka RCX2R' where X is halogen)

I sometimes using this stategy in organic synthesis too.
 
I was just looking into this just the day before last, interestingly. I was curious as to why a lot of DRI ligands use di-chloro substitutions when they're being optimized but not di-bromo,
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I seem to recall that dichloro compounds tend to be more active in general as DRIs, also sourcing required precursors is probably easier with the 3,4-dichloro group so abundant in drugs today (e.g. sertraline)
 
Memantine said:
How does it cause CNS depression? Is it because of hyperchloremia? Or suppression of the thyroid?

How toxic is bromide?
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The functional groups of the compound are the determinant not bromine


Some Bromine compounds cause CNS stimulation

2-CB, bromo-dragonfly, bromomescaline

Others, have CNS depressant effects

Bromazepam -- a brominated benzodiaepine
 
I think you misunderstand - "free" ionic bromide, like in sodium bromide, is actually bioactive as a sedative. It's got a very long half life and a rather small therapeutic index though, so it's not used much if at all any more.
 
sekio said:
I seem to recall that dichloro compounds tend to be more active in general as DRIs
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Perhaps in general, but the methylphenidate bromo-aryl is more active than chloro, they have para & meta solo in either of the chloride & bromide and of those I've seen all examples and datasets on all four, but for the di-substituted I've only seen di-chloro-MPH and never once seen di-bromo-MPH attested to; I'm just curious as to why that is. It is only *slightly* more active than the chloro, but regardless.
 
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Nagelfar said:
Perhaps in general, but the methylphenidate bromo-aryl is more active than chloro, they have para & meta solo in either of the chloride & bromide and of those I've seen all examples and datasets on all four, but for the di-substituted I've only seen di-chloro-MPH and never once seen di-bromo-MPH attested to; I'm just curious as to why that is. It is only *slightly* more active than the chloro, but regardless.
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I'm guessing this has to do with the fact that drug development is often guided by ligand efficiency metrics. Bromine and chlorine often have similar effects on affinity but bromine is heavier; adding two bromines is therefore a ligand efficiency nightmare.
 
serotonin2A said:
I'm guessing this has to do with the fact that drug development is often guided by ligand efficiency metrics. Bromine and chlorine often have similar effects on affinity but bromine is heavier; adding two bromines is therefore a ligand efficiency nightmare.
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Even though a slight derailment on my part, I thank you for the response I can see the rationale there.
 
sekio said:
I seem to recall that dichloro compounds tend to be more active in general as DRIs, also sourcing required precursors is probably easier with the 3,4-dichloro group so abundant in drugs today (e.g. sertraline)
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What kind of dichloro stimulants have you seen? Fluorine 2,3,4 - monosubstituted amphetamines and a couple dichloro-cocaine analogs.... Oh and 3,4-dichloromethylphenidate, which seems to be the only true dichloro DRI listed since the cocaine analogs are more SNRI's than SNDRI's. The popular ones now a days seem more normal like dextroamphetamine, dextromethamphetamine, cocaine, methylphenidate, and 4-fluorophenmetrazine.
 
Bromide is no fun - it takes days to reach an effective dose and it's TI is rather narrow. It was better than nothing when there WAS nothing else but it was quickly dropped because even things like chloral hydrate are safer.
 
The bromides were the first seditatives synthesized, what then followed were easy sulfur containing compounds and things like chloral.
 
I forget the pharmacore of those early sulfur hypnotics. That they weren't covered by the MoDA suggests that their isn't much abuse potential. But their are odd compounds that haven't been controlled like chlormezanone and clomethiazole. I think the former is still widely used in China but the latter is almost extinct outside of in-patient treatment of alcohol-dependent patients.
 
Ah, thank you. I hadn't seen the cyclic example. 1λ6,5λ6,2,4-dithiadiazinane-1,1,3,5,5-pentone. Now, does one 6,6-disubstitute much as one substitutes barbituric acid? The others have a dimethyl, methylethyl, diethyl (and so on).

That would require some interesting chemistry. US Patent 396526A is the index paper. I'm pretty sure that others sought to find related compounds that did not fall under this patent.

The cyclic one would be fascinating to study by following the QSAR or barbiturates and seeing how much it deviates. I think allyl/sec-butyl is the most potent of the barbiturates until one begins to add bromine atoms to those chains and then the MW goes up so ARE they any more potent.
 
Do you guys think hydrobromide salts of drugs have, when taken in a certain amount upwards, will have bromide pharmacology effects? DXM FAQ lists bromide poisoning as a theoretical side effect, but does this happen?
 
plumbus-nine said:
Do you guys think hydrobromide salts of drugs have, when taken in a certain amount upwards, will have bromide pharmacology effects? DXM FAQ lists bromide poisoning as a theoretical side effect, but does this happen?
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So i was looking at brominism cases to see the doses involved. This recent case involved a lady taking about 6 g per day of calcium bromogalactogluconate for 1.5 months. This carrier molecule is smaller than dextromethorphan, so for every gram of dxm hbr there would be less bromine than in a gram of calcium bromogalactogluconate.

So to get an equal severity of symptoms you would need to be dosing well in excess of 6 grams of dxm hbr per day for a few months. You would obviously have other more pressing issues than brominism.

That being said, it is certainly possible that people with long term multi gram per day dxm habits are experiencing some minor enhancement of chloride channel function from all the bromide.

Edit: source

pubmed.ncbi.nlm.nih.gov

Bromism from daily over intake of bromide salt - PubMed

Bromide intoxication today is an infrequent disease, but preparations containing bromide are still available in nonprescription compounds, on the French market. We report a casewith bromide intoxication due to daily over intake (approximately 20 tablets per day; i.e. total elemental bromide...
pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
 
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