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

[purplehaze147]

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

Barbituates, Z-drugs, and propofol do, but are mainly PAMs (at least the first two, I'm not sure about propofol's activity as a PAM, but given its abuse potential I'd say it is). Primary agonists include: GABOB, isoguavine, quisqualamine, gaboxadol, bamaluzol, the better known prodrug progabide's active metabolite SL-75102, ibotenic acid (also in amanita mushrooms like muscimol but toxic).

 

[purplehaze147]

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

It has more hydrogens to form hydrogen bonds with

 

[emkee_reinvented]

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.

but does the GABA that crosses the BBB activate's the GHB receptor or does the body creates its own GHB is what I am curious about.

 

[izo]

GABA is synthesized within the CNS from several amino acids that do cross the BBB.

Can somebody shed some light onto whether GABA sythesized via the glutamate decarboxylase pathway plays a significant role?

 

[cdin]

Barbituates, Z-drugs, and propofol do, but are mainly PAMs (at least the first two, I'm not sure about propofol's activity as a PAM, but given its abuse potential I'd say it is). Primary agonists include: GABOB, isoguavine, quisqualamine, gaboxadol, bamaluzol, the better known prodrug progabide's active metabolite SL-75102, ibotenic acid (also in amanita mushrooms like muscimol but toxic).

Nice list! Afaik ibotenic acid is a glutamate analogue, glutamate receptor agonist and it’s toxicity comes from the stimulation of glut sites. Whereas muscimol is a pure gabaA agonist. I thought it was the only non-Pam. Going to have to research the rest of these

 

[cdin]

Can somebody shed some light onto whether GABA sythesized via the glutamate decarboxylase pathway plays a significant role?

I thought taurine was the main precursor for GABA?

 

[purplehaze147]

but does the GABA that crosses the BBB activate's the GHB receptor or does the body creates its own GHB is what I am curious about.

The body makes most of its own neurotransmitters if as long as they aren't simply an essential amino or essential fatty acids; I'm nearly certain all are unless I'm missing an exception. There's no neurotransmitter we need to consume from our diet (excluding essential amino and fatty acids and vitamins).

They all come from amino acids, fatty acids, cholesterol, vitamins, minerals and sometimes carbs, but they're mostly for energizing nicotinamide and charging up adenosine to ATP. Carbs are powering the whole cycle actually, but not used directly in synthesis usually, sometimes to metabolize a molecule to increase solubility via glycogenolysis (or something like that) therefore increasing excretion rate, but they're not very good for functional groups.

The primary ligand for the GHB receptor is GHB, possibly a more selective contender without the GABA-B agonism, I forget the name, but that doesn't mean much. It's whichever endogenous transmitter causes the most activity at the site while sober basically.

GHB is made from succinate acid which is produced in the citric acid cycle. GHB then produces GABA and glycine, GABA produces glutamate etc. They all originated (or the vast majority) from an amino acid that crosses the BBB like lysine and other chained non-polar amino acids.

Edit: I mistakenly forgot to mention that reactions in this combination of cycles can go in reverse. Like usually glutamine crosses the BBB the make glutamate, which is the primary GABA precursor. GABA can turn into glutamate or glutamic acid in some situations too. But GHB is synthesized from succinic acid which then the GHB acts as a precursor to GABA.

 

[purplehaze147]

I thought taurine was the main precursor for GABA?

Glutamate is definitely the primary precursor. Glutamine freely crosses the BBB and is converted to glutamate, then GABA, then back to the citiric acid cycle as succinic acid. It can also be produced from succinic acid, to GHB, the GABA.

Being that taurine (-)O3S-CH2-CH2-NH3(+) and GABA (-)COO-CH2-CH2-CH2-NH3(+) are at biological pH, I don't think it can directly react to as a precursor to GABA in a one step reaction... Possible a with ketone body.. I'll edit in shame if I'm wrong that's how confident I am.

 

[emkee_reinvented]

The body makes most of its own neurotransmitters if as long as they aren't simply an essential amino or essential fatty acids; I'm nearly certain all are unless I'm missing an exception. There's no neurotransmitter we need to consume from our diet (excluding essential amino and fatty acids and vitamins).

They all come from amino acids, fatty acids, cholesterol, vitamins, minerals and sometimes carbs, but they're mostly for energizing nicotinamide and charging up adenosine to ATP. Carbs are powering the whole cycle actually, but not used directly in synthesis usually, sometimes to metabolize a molecule to increase solubility via glycogenolysis (or something like that) therefore increasing excretion rate, but they're not very good for functional groups.

The primary ligand for the GHB receptor is GHB, possibly a more selective contender without the GABA-B agonism, I forget the name, but that doesn't mean much. It's whichever endogenous transmitter causes the most activity at the site while sober basically.

GHB is made from succinate acid which is produced in the citric acid cycle. GHB then produces GABA and glycine, GABA produces glutamate etc. They all originated (or the vast majority) from an amino acid that crosses the BBB like lysine and other chained non-polar amino acids.

Edit: I mistakenly forgot to mention that reactions in this combination of cycles can go in reverse. Like usually glutamine crosses the BBB the make glutamate, which is the primary GABA precursor. GABA can turn into glutamate or glutamic acid in some situations too. But GHB is synthesized from succinic acid which then the GHB acts as a precursor to GABA.

Nice explanation, a bit above my head. But a very good readable description. So the body make's trace amount's of GHB via that cycle. So that cleares up why we have that receptor in the first place.

What i once read was that in the blood, referring to ingested GHB/ GBL. As a drug, is that they are in equilibrium in the blood. So there is always some conversion going on. GHB to GBL and back.

 

[izo]

Gbl gets partially hydrolized in aqueous solution to ghb, depending on the ph, the higher it is the more ghb is being build:

The chemical interconversion of GHB and GBL: forensic issues and implications - PubMed

In this work, the interconversion of GHB and GBL in a variety of aqueous media was studied. The effects of solution pH and time were determined by spiking GHB or GBL into pure water and buffered aqueous solutions, and determining the GHB and GBL contents at various time intervals. The degree of...

pubmed.ncbi.nlm.nih.gov

I don’t know if the esterases in the blood do work in the Reverse way, producing esters. Just read that some enzymes do this.

 

[purplehaze147]

Gbl gets partially hydrolized in aqueous solution to ghb, depending on the ph, the higher it is the more ghb is being build:

The chemical interconversion of GHB and GBL: forensic issues and implications - PubMed

In this work, the interconversion of GHB and GBL in a variety of aqueous media was studied. The effects of solution pH and time were determined by spiking GHB or GBL into pure water and buffered aqueous solutions, and determining the GHB and GBL contents at various time intervals. The degree of...

pubmed.ncbi.nlm.nih.gov

I don’t know if the esterases in the blood do work in the Reverse way, producing esters. Just read that some enzymes do this.

Lactonases in the blood rapidly convert GHL to GHB. GBL's higher lipophilicity even allows for a faster come up. It

It can go vice versa too. Below a certain pH it will also get hydrolyzed to GHB. I may sound crazy but everything is an acid or a base depending on what other compounds it's around. I the presence of a strong acid with a high enough concentration, the GBL is a base, with a base it acts as an acid.

And also equilibrium reactions are cool.l, but it seems most production of GHB starts from succinic acid and that GBL is barely produced in tace amount if that.