Barbiturates are Chloride Channel Openers, the only ones in existance!

[Anxious.Individual]

While most people don't know this, barbitirates have a binding site in any chloride channel, and once bound there it forces the channel open, letting the chloride anions flow, and on top of that it increases the influx of already flowing chloride anions. There is no other drug or class of drugs currently to have this capability!

This means that barbiturates fully activate GABA-A, GABA-C and Glycine receptors, with much higher efficiency than an agonist!

However barbitirates only have moderate affinity for Cl channel sites, so only large doses will produce this effect, the most potent barbiturate by weight is actually Phenobarbital. Around 100mg of Phenobarbital is enough to produce this effect, for less potent ones however, such as Amobarbital, around 250mg is required.

Also, here is the full description of Barbiturate pharmacology:

Effect on GABA-A: Since barbs only open the Cl channel and fully activate the receptor at larger doses, moderate doses(such as 60mg Phenobarbital) have a separate effect on the GABA-A receptor. There are two allorestic binding sites for barbiturates on the 2 αβ sub-units, the first one is right next to the GABA binding site, and once activated by a barbiturate it prevents GABA from being diffused (detached) from the receptor, meaning that GABA stays on the receptor for much longer. the second barb allorestic site is near the bottom of the sub-unit, and once it's activated by a barbiturate, it increases the affinity of the GABA-A receptor for GABA, thus making the GABA much more likely to bind.

Effect on GABA-C: Barbiturates only affect this receptor at larger doses. They fully activate it by opening the Cl channel and keep it activated for time that is dependent on half-life of the barbiturate used. Such activation of GABA-C is responsible for the blurred vision that barbitirates cause at large doses.

Effect on Glycine receptors: Same as with GABA-C, barbs at larger doses open the Cl channel and fully activate receptor. This action at Glycine receptors is also responsible for the extra motor-impairing and muscle relaxing effects of barbitirates.

Barbiturates also decrease glutamate through a variety of mechanisms,

Barbiturates, both antagonize and block the channels of AMPA and Kainate receptors.

Barbiturates also block the channels of nACh receptors and block the channels of all sub-types of 5-HT3 receptors.


Well, as you can see, they are one hell of a depressant! This is why it's so easy to OD on them. I hope you found this info interesting.

Anxious.Individual

 

[serotonin2A]

It is certainly true that barbiturates activate ligand-gated chloride channels. But barbiturates don't bind to all chloride channels. Voltage-gated chloride channels are not activated.

 

[aced126]

Nice info, source? Also serotonin, you said barbiturates activate v-gated cl- channels but then go on to say v-gated cl- channels aren't activated. What do you mean by this?

 

[Nagelfar]

I know benzos and barbs have different MoA, barbs maintain the channel in open conformation longer, and benzos open channels more frequently, am I right? Any known compounds with both methods of action in one? That'd be a rather powerful CNS depressant.

 

[belligerent drunk]

AFAIK benzos don't open chloride channels, they only change the conformation of the receptor to increase GABA affinity.

 

[Nagelfar]

AFAIK benzos don't open chloride channels, they only change the conformation of the receptor to increase GABA affinity.

Are they mutually exclusive ligands? Meaning, if the conformation of a particular receptor has increased affinity, would that be cumulative to additionally having the channel open at the same specific site or would that be, intuitively, redundant?

 

[serotonin2A]

Nice info, source? Also serotonin, you said barbiturates activate v-gated cl- channels but then go on to say v-gated cl- channels aren't activated. What do you mean by this?

I meant to write "ligand-gated"

 

[serotonin2A]

I know benzos and barbs have different MoA, barbs maintain the channel in open conformation longer, and benzos open channels more frequently, am I right? Any known compounds with both methods of action in one? That'd be a rather powerful CNS depressant.

You have that right. It would be difficult to develop a ligand that did both because it would either have to bind to both sites or to a different allosteric site that induced both effects.

 

[Nagelfar]

AFAIK benzos don't open chloride channels, they only change the conformation of the receptor to increase GABA affinity.

You have that right. It would be difficult to develop a ligand that did both because it would either have to bind to both sites or to a different allosteric site that induced both effects.

Any insight from the peanut gallery here on the exact difference: Yea, or nay, on the diff' in MoA

 

[AlphaMethylPhenyl]

the peanut gallery defers to sekosaurus

 

[Nagelfar]

the peanut gallery defers to sekosaurus

There we have it, sekio, we have petitioned your mental lexicon on this one.

 

[serotonin2A]

Any insight from the peanut gallery here on the exact difference: Yea, or nay, on the diff' in MoA

BZs don't appear to act by increasing the affinity of the receptor for GABA. Rather, they shift the equilibrium toward a preactivated state. Thus, when GABA binds, it is able to open the channel at a higher frequency.

http://m.jneurosci.org/content/32/17/5707.full

Barbiturates, by contrast, allow the channel to stay open for longer periods of time after the receptor is activated by an orthosteric agonist (GABA, etc). They also induce channel opening if present at high concentrations.

 

[Kittycat5]

Any insight from the peanut gallery here on the exact difference: Yea, or nay, on the diff' in MoA

I think it is still generally taught that benzodiazepines do increase the frequency of chloride channel opening and barbiturates increase the mean time the channel remains open.

Benzos increase the affinty of GABA at the receptor by slowing its unbinding from the receptor. Interestingly, at high concentrations of GABA, as seen synaptically, it is not an increase in amplitude of inhibitory postsynaptic currents but rather a prolongation of IPSC decay that enhances GABA affinity, which is consistent with slower unbinding as the mechanism of benzo action. It is not so much they increase the frequency of the open state of the chloride channel, but decrease the amount of time it is in a closed state which has the same net effect. Some agrue that this model is innacurate for synaptic GABAa receptors but is perfectly fine for extrasynaptic receptors where GABA concentration is lower and may be a good way of thinking about tonic GABA conductance. It has been proposed that a simultaneous opening of many synaptic channels may be the proper mechanism of benzos action but this is not mainstream.

Barbiturates, on the other hand, are still thought of to increase the duration in which the chloride channel is open. They are much more promiscuous than benzos, which the alpha and gamma subunits of the GABAa receptor are needed in some form to work. Barbs seem to work anywhere a GABAa receptor is located despite its conformation. They cause fewer openings of the short duration open states (O1 and O2) and more of the long duration state O3. This results in a longer mean time the chloride channel is open.

And ganaxolone may be a drug that both increases the duration and frequency of opening, but I am rather unfamiliar with it. Perhaps someone can comment if this is conceivable.

 

[serotonin2A]

It is not so much they increase the frequency of the open state of the chloride channel, but decrease the amount of time it is in a closed state which has the same net effect.

I don't really understand the difference. You are talking about cause (change in channel kinetics) and effect (change in the frequency of channel opening). If you look at single channel recordings, you can clearly see that the channel fluctuates between conductance and non-conductance states more often in the presence of benzodiazepines, hence why people say that the frequency of channel opening increases.

 

[clubcard]

There IS a 'barbiturate site' on the GABA gates but not just barbiturates fit into it. Picrotoxin binds to the same site (bad) and so does clomethiazole. The carbamates act indirectly on the site.

 

[serotonin2A]

There IS a 'barbiturate site' on the GABA gates but not just barbiturates fit into it. Picrotoxin binds to the same site (bad) and so does clomethiazole. The carbamates act indirectly on the site.

Picrotoxin and barbiturates seem to bind to distinct sites. The sites were thought to be identical at one time but that is no longer the case. The first evidence came from binding studies (follow the link below), and this interpretation was eventually comfirmed with cloned channels.
.
http://www.ncbi.nlm.nih.gov/m/pubmed/2981283/?i=3&from=Maksay ticku

 

[Nagelfar]

BZs don't appear to act by increasing the affinity of the receptor for GABA. Rather, they shift the equilibrium toward a preactivated state. Thus, when GABA binds, it is able to open the channel at a higher frequency.

http://m.jneurosci.org/content/32/17/5707.full

Barbiturates, by contrast, allow the channel to stay open for longer periods of time after the receptor is activated by an orthosteric agonist (GABA, etc). They also induce channel opening if present at high concentrations.

So I was correct and BD in error. BD care to defend your side?

 

[belligerent drunk]

I have to admit I wasn't familiar with such details. I thought that barbiturates could open the channel by themselves, without GABA, among other things whereas BZDs could only alter the action of GABA at the receptor, not being able to open it on their own. Sorry for providing wrong information!

 

[dopamimetic]

Is there anything known about how this effects can be reversed - leading to the possibility for a treatment for GABAergic addiction (including ethanol)?

The point about flumazenil & adenosine which allows people to settle on a much lower dose of a BZD than previously is very intriguing.

 

[serotonin2A]

Is there anything known about how this effects can be reversed - leading to the possibility for a treatment for GABAergic addiction (including ethanol)?

The point about flumazenil & adenosine which allows people to settle on a much lower dose of a BZD than previously is very intriguing.

Here we are talking about the acute effects of benzodiazepines and barbiturates. You can certainly block their acute effects, but then no one would want to take them because they wouldn't have any effect.