Benzos Bet you probably don't know the endogenous ligand for the benzodiazepine receptors on the GABAA complex.

[purplehaze147]

This information is kept very quiet for some reason, but it's the nucleobase inosine that's the endogenous ligand. It's a rarely utilized one in RNA (and DNA?) - the primary ones are only AC(T/U)G and make up... I'd have to estimate 99%+ of all RNA/DNA (only counting nucleic acids).

Nicotinamide may also play a role.

Endogenous PAM's of GABAA which don't bind to the benzodiazepine receptors are neurosteroids, vitamin B6, and ....a few others a can't remember at the moment.

Every receptor should have a natural ligand in the body. It doesn't make receptors for no reason.

 

[emkee_reinvented]

GHB?

 

[blazR]

GHB?

GHB is also endogenous...

 

[izo]

Source?

 

[emkee_reinvented]

Source?

Lazyness on my side, love Bluelight for that selfcorrecting mecanism.

By know means I am knowledgeable btw. But this is what I found. But I have to admit that an receptor has to have an function other then for us to get high on GHB.

"GHB, a naturally occurring inhibitory neurotransmitter that binds to γ-aminobutyric acid B (GABA-B) and GHB receptors"

from https://www.sciencedirect.com/topics/medicine-and-dentistry/ghb-receptor

But the missing dot is: does the body produce a GHB like substance that bind's to that receptor? To this day I have wondered about this.

 

[thegreenhand]

benzodiazepines are generally understood to be (positive) allosteric modulators. thus, their binding site doesn't necessarily have to 'have a natural ligand in the body'

from wikipedia (yeah yeah i know hate on it all you want, but for these sorts of things it's useful):

The site that an allosteric modulator binds to (i.e., an allosteric site) is not the same one to which an endogenous agonist of the receptor would bind (i.e., an orthosteric site).

found here

that's not to say there isn't an endogenous ligand. but the presence of an allosteric site is not sufficient to conclude that one for sure exists.

 

[emkee_reinvented]

https://pubmed.ncbi.nlm.nih.gov/22316155/

Allosteric vs orthosteric. I learned something today.

 

[izo]

Wikipedia states no endogenous ligand for the ghb receptor but as already mentioned ghb is produced in trace amounts in the human body.

 

[emkee_reinvented]

Wikipedia states no endogenous ligand for the ghb receptor but as already mentioned ghb is produced in trace amounts in the human body.

That was the reason for this thread right?

Is there a body produced ligand for a certain receptor. But if you mention GHB being produced by the body. Can you back that up with some scientific paper's?

 

[izo]

Ive Reader it somewhere but dont have Access to my paper library. Quick Google Search:

Endogenous Gamma-Hydroxybutyrate in Postmortem Samples - PubMed

Gamma-hydroxybutyrate (GHB) is a naturally occurring molecule present in the human body as a catabolite of the neurotransmitter gamma-aminobutyrate (GABA). In the USA, GHB has a history of being manufactured illicitly and abused, with misguided proposed benefits for the body-building community...

pubmed.ncbi.nlm.nih.gov

Gamma hydroxybutyric acid (GHB) concentrations in humans and factors affecting endogenous production - PubMed

The endogenous nature of the drug of abuse gamma hydroxybutyric acid (GHB) has caused various interpretative problems for toxicologists. In order to obtain data for the presence of endogenous GHB in humans and to investigate any factors that may affect this, a volunteer study was undertaken. The...

pubmed.ncbi.nlm.nih.gov

 

[purplehaze147]

GHB?

No it binds as an agonist. There's specific sites on the GABAA complex that GABA does not bind to. It's noncompetitive with GABA. GHB is a straight up agonist of only GABA-B receptors, and binds on the same receptor as GABA, unlike a positive allosteric modulator like agonists of the benzodiazepine sites.

 

[purplehaze147]

benzodiazepines are generally understood to be (positive) allosteric modulators. thus, their binding site doesn't necessarily have to 'have a natural ligand in the body'

from wikipedia (yeah yeah i know hate on it all you want, but for these sorts of things it's useful):



found here

that's not to say there isn't an endogenous ligand. but the presence of an allosteric site is not sufficient to conclude that one for sure exists.

Yeah it kind of does, every allosteric site has an endogenous ligand unless it hasn't been found yet in rare instances. Neurosteroids, indosine, and a few other endogenous compounds bind to the allosteric sites of the GABAA chloride ion channel complex.

 

[izo]

and binds on the same receptor as GABA

I always wondered how as GABA Has this Basic amine function whereas ghbs oh group is slightly acidic.

 

[purplehaze147]

Wikipedia states no endogenous ligand for the ghb receptor but as already mentioned ghb is produced in trace amounts in the human body.

trans-4-hydroxycrotonic, AKA T-HCA, is likely the endogenous ligand. GHB is also an endogenous ligand, it just bonds to GABA-B as well, unlike T-HCA. Another exame of an endogenously occuring drug that is produced in the body is morphine.

 

[purplehaze147]

I always wondered how as GABA Has this Basic amine function whereas ghbs oh group is slightly acidic.

GABA is gamma-aminobutyric acid. It has an acidic carboxyl functional group and a basic amino group, so therefore it is both an acid and a base depending on what it's reacting with. Receptor binding is usually hydrogen bonding, so the R-OH group of GHB and the R-NH3+ group of GABA are going to bind a hydrogen bond with an oxygen lacking a proton (hydrogen) in the same way pretty much. The amino group of GABA is likely the cause of its higher binding affinity than GHB to the GABA-B receptor.

 

[Kellsee]

^^yeah that's what all I was gonna say but he beat me to it

 

[izo]

The amino group of GABA is likely the cause of its higher binding affinity than GHB to the GABA-B receptor.

That i dont really get atm but the Rest makes sense. Thx

 

[emkee_reinvented]

No it binds as an agonist. There's specific sites on the GABAA complex that GABA does not bind to. It's noncompetitive with GABA. GHB is a straight up agonist of only GABA-B receptors, and binds on the same receptor as GABA, unlike a positive allosteric modulator like agonists of the benzodiazepine sites.

My reply was mainly about the GHB receptor. As example of why a receptor is there while the body's GABA that crosses the BBB only are little amount's. But indeed activates that receptor.

GHB is mainly a GABA-B agonist, the sedative effect. And a GHB receptor agonist. Which explain's the stimulating pro sexual action. Via the dopamin pathway.

 

[cdin]

Afaik - the only true EXOgenous ligand that truly hits GABAA and is not a PAM is muscimol. Glorious muscimol.

 

[purplehaze147]

My reply was mainly about the GHB receptor. As example of why a receptor is there while the body's GABA that crosses the BBB only are little amount's. But indeed activates that receptor.

GHB is mainly a GABA-B agonist, the sedative effect. And a GHB receptor agonist. Which explain's the stimulating pro sexual action. Via the dopamin pathway.

GABA is synthesized within the CNS from several amino acids that do cross the BBB. Other examples include dopamine, serotonin, epinephrine, glutamate and many others.