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Why do high potency benzodiazepines bind to certain brain regsions/receptors ?

K

Kdem

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Mar 14, 2015
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(alprazolam, lorazepam, clonazepam)

Especially with lorazepam and clonazepam there are references of these drugs having an effect on the brain stem and spinal cord. It was hard to find sources, here:

https://books.google.nl/books?id=1W...gh potency benzodiazepines brain stem&f=false it is stated that areas like the brain stem are relatively poor in benzodiazepine receptors. Really ? The source is from 1995.

Again, why exactly are high potency (low Ki) benzodiazepines 'relatively selective' ? Is anything known ?
 
There is the TSPO receptor that was formally a peripheral benzo receptor, and different benzos have affinity for gaba a receptors with different subunits as well. If some benzos don't cross the bbb as well as others then that could be more of a peripheral acting benzo
 
Again, why exactly are high potency (low Ki) benzodiazepines 'relatively selective' ? Is anything known ?
Click to expand...

What do you mean by that (high potency benzodiazepines being 'relatively selective')? Selective towards what?
 
^Yeah I was thinking that he was meaning selective towards the PNS since he was talking brainstem and spinal cord, in which case PK factors could result in more peripheral binding and muscle relaxation even if the BZ receptorTSPO affinity is the same.

But maybe he is talking about the fundamentals of affinity/intrinsic efficacy and the different gaba A subunit containing receptors?
 
@adder, @ cotcha,

Selective to either specific receptors and/or brain areas.

From what I read in several studies high potency benzodiazepines (especially clonazepam, probably also lorazepam) are 'relatively selective' (binding to the entire brain, but having a particulary high affinity for certain brain regions) for the brain stem, spinal cord, I've probably seen references to the limbic system as well, possibly more. Effects on the brain stem seem the most obvious and common.
 
Because the physical properties of their molecule structure allow easier binding to those receptors
 
^right

OP, essentially there are different GABA-A receptors that are shaped a bit differently, and different benzos will bind a bit better or worse to those GABA A channels because not all GABA A receptors are the same

If all GABA-A receptors were indeed the same then there wouldn't be much difference from benzo to benzo in terms of affinity for different receptors, but there could still be differences in instrinsic efficacy - which determines not really what gaba-a receptor a benzo can bind to but rather how much it can activate the receptor when it does actually bind there
 
Still, is it known which properties are relevant ? The alpha2/alpha3 subunit ? Diazepam binds to those subunits as well, to a lesser degree. If that´s the case, do the high potency benzodiazepines have an affinity for those subunits that is so much higher than the equivalency tables suggest ? Or is the Ki value rather than alpha2/3 ?
 
I'm not familiar with the benzos differential affinity for different subunit containing gaba-a channels but the other thing to keep in mind is the intrinsic efficacy could vary even if the affinity is similar
 
I feel I lack a formal eduction in biochemistry ...

There is a propensity (probability?) of a molecule to bind to a certain receptor (for example, a preference for alpha2, apha3 subunits), and the strength/exerted force that is put on a certain receptor. I take it the former depends on the chemical structure, and the latter is Ki ? Is that right ?

Cotcha, good remark. I was not familiar with 'intrinsic efficacy'.

Brain chemistry, not something to be messed with ... especially by doctors.
 
Yeah you can basically think about affinity (Ki) as how likely a ligand is to bind to a receptor, and intrinsic efficacy is what effect the ligand actually has on the receptor in terms of activating it or blocking it, or functioning as a positive allosteric modulator like benzos are
 
Cotcha,

I just got a bit more confused !

Ki ... ´how likely a ligand is to bind to a receptor´ I recall the phrase that drugs with a low Ki ´bind tightly´ and was under the impression that that was about strength/exerted force on a receptor. You´re saying it´s probability ?

´intrinsic efficacy´ is indeed a term I only recently learned about. Too bad that not much is known about that (benzos).
 
Reading a few things again ...

For example, the van der waals forces ... is that part of Ki ? Or Intrinsic efficacy ?
 
Ki, or affinity, is determined by an equation that basically considers

1. how quickly a ligand binds to a receptor
2. how long it stays there

So if a ligand binds quickly and then stays a while once bound, it has high affinity. If it binds slowly and unbinds quickly, then it would have low affinity and wouldn't be very good at activating the receptor.

Drugs can interact with the receptors in different ways, for example very high affinity ligands can form covalent bonds with receptors and stay bound almost indefinitely (until the receptor complex recycles). But mostly they're just interacting with residues, however I don't know too much about chemistry.

So there may be some spots on the receptors that the ligands fit neatly into (like a key in a lock) and then some interactions cause the receptor to change shape a bit (a conformational change) which then produces some change in the receptors, possibly activating it all the way like the endogenous ligand (full agonism), activating it part of the way (partial agonism), or not activating it at all (antagonism).

But ligands can have high affinity for a receptor and just sit on top of it, not actually activating it (the ability to activate a receptor takes some intrinsic efficacy). So the affinity is how attracted a drug is to the receptor, while the intrinsic efficacy is how good the drug is at actually activating the receptor once its bound.

You can have a drug that is great at binding to receptors but doesn't activate them (a high affinity antagonist) and a drug that is great at activating receptors but hardly ever binds (a low affinity agonist).

As a caveat, benzos aren't really agonists IIRC, they are known as positive allosteric modulators. They function by binding to a spot on the GABA-A complex that, when the benzos bind there, increases the affinity of endogenous GABA for the GABA-A receptor.

So benzos work by enhancing GABA's affinity, if you will. At least I don't think the benzos have much of their own intrinsic efficacy (in other words, benzos may not actually do much in the absence of endogenous GABA). Whereas I believe barbiturates have some intrinsic efficacy.

Hope this was helpful
 
@Cotcha,

Thank you.

Re: agonisms/POMs, benzodiazepines bind at the (the interface of ? terminology) subunits 1,2,3,5, a beta unit and a gamma unit of the GABAA receptor complex. In theory there may be some other effects by binding to the peripheral benzodiazepine receptor/TSPO. But disregarding the latter, is the action at the former not a form of intrinsic efficacy ? With indeed differences, desmethyldiazepam (the active metabolite of Tranxene and a metabolite of diazepam) is a partial agonist (´of the benzodiazepine receptor´) if I recall correctly, and diazepam and clonazepam are full agonists ? (I just checked https://en.wikipedia.org/wiki/Intrinsic_activity) But maybe I´m wrong about that. There is POM vs. (full) agonist, perhaps a bit confusing.
 
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A good way to conceptualize the difference between an agonist with real intrinsic efficacy and a PAM is that a PAM won't do anything in the absence of the endogenous transmitter (in this case GABA) because a PAM is just increasing the affinity of the endogenous transmitter for the receptor

I'm not sure if any of the benzos have any appreciable intrinsic efficacy of their own, and I would watch out when the words "agonist/partial agonist" are used in reference to benzos because that may just be a mix up of terms, but I'm really not familiar with the benzos.

A way to study the intrinsic efficacy of benzos would be to see what the benzos do to the receptors in the absence of GABA in vitro, if benzos still inhibit cell firing in the absence of any GABA then that leans towards that benzo having some efficacy, but who knows whether its appreciable or not
 
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