GHB Receptor Ligands

[3DQSAR]

Sci-Hub | Novel Cyclic -Hydroxybutyrate (GHB) Analogs with High Affinity and Stereoselectivity of Binding to GHB Sites in Rat Brain. Journal of Pharmacology and Experimental Therapeutics, 315(1), 346–351 | 10.1124/jpet.105.090472

I'm old enough te remember a time before the GHB receptor had been identified.

As I always make clear, affinity ≠ efficacy . It's also worth noting that within a series, the compound with the highest affinity may not be the compound with the lowest EC50 (highest potency). Now you have to bear in mind that when I studied, docking calculations were not calculated but I suspect that it IS the docking conformation that might be part of the reason why compounds with a lower affinity might still be more potent.

The above paper has a lot of references. I am happy to dig them all out if that is what people want.

Now I didn't like GHB for manifold reasons, among them was the caustic taste, feeling of having been poisoned and not least the fact that there seems to be an ideal dose for each person. I presume this to be a playoff between sought activity and side-effects. I think it also worth noting that many sources simply describe GHB as an 'intoxicant' and it does appear that GHB has GABAgenic activity more general than it's simple activity at a single receptor.

The mode(s) of toxicity displayed by GHB appear to be due to it's action on the GABA receptors. To be clear, drugs like benzodiazepines act as positive allosteric modulators rather than acting as a GABA mimic.

But (R)-HOCPCA had the highest affinity (0.11 µM) compared to that of GHB (4.3 µM) at the GHB receptor.

I note that HOCPCA is unsaturated, a feature seen in H-TCA which apparently does not act as a CNS depressant.

So I merely offer this as a starting point with the aim of promoting discussion.

 

[Smyth2]

Draft:GET-73 - Wikipedia

en.wikipedia.org

 

[3DQSAR]

Novel Agents for the Pharmacological Treatment of Alcohol Use Disorder - PMC

Alcohol use disorder (AUD) is a highly prevalent but severely under-treated disorder, with only three widely-approved pharmacotherapies. Given that AUD is a very heterogeneous disorder, it is unlikely that one single medication will be effective for ...

pmc.ncbi.nlm.nih.gov

I note that GET73 is mentioned as being a GBB analogue but without reference. But I note an earlier patent (EP0932597A1) from the same group specifically mentions it's chemical similarity in the title. and indeed that patents cite earlier works where GHB is actually proposed for certain treatments.

The question I can't see an answer for if is GET73 acts as a GABAgenic compound and/or acts on the GHB receptor. I'm not saying it doesn't just that I didn't spot it.

It appears that as a medication it's completed stage 1 or even stage 2 trials (depending on which source you read) and I note the stated mechanism of action is as a mGluR5 negative allosteric modulator.

I've note over the decades quite a few medications arrive that are aimed at dealing with alcohol dependence. It seems that doctors have (possibly rightly) begun to avoid medications that can themselves produce dependence, at least in out-patient settings. So I find this an interesting oddity.

 

[emkee_reinvented]

GHB is very active at the GABA-b site besides the GHB receptor.
Oxytocin release, wasn t that one of its actions to ? I check that.
No Oxytocin effects.

But overal it was apparent when you WD, Benzo s, like with Alcohol WD.
Just coverup but don t really adress the problem while Alcohol and GHB.
Are good substitutes of each other,
hence the early use of GHB for Alcohol detox.

Sadly abandoned.

 

[negrogesic]

Now I didn't like GHB for manifold reasons, among them was the caustic taste, feeling of having been poisoned and not least the fact that there seems to be an ideal dose for each person.

Sodium GHB isn't always caustic if buffered properly when dissolved in water. Years ago there was a Canadian source (long defunct) that sold sodium GHB in crystalline form (very hydroscopic and even had a certain wetness despite being in a vacuum sealed bag. The place also sold meperidine powder believe it or not (which I actually thought was bunk; turns out it was just my methadone tolerance, and years later I found out that the meperidine was in fact legit).

Anyway, as far as GHB, I still agree with the feeling poisoned part. Though not as noxious as GBL or 1,4-BD, sodium GHB can certianly still produce a state where one feels "poisoned". And while less unpredictable than 1,4-BD, sodium GHB is still unpredictable. You'll be feeling great and you take a little more and suddenly you're feeling horrible. Meanwhile, you take a much larger dose a month later, and zero problems.

I think the GHB "sickness" and extreme nausea must be mediated by something more than the GABA-B receptor, since it's hard to replicate the same sickness with selective GABA-B agonists like baclofen (which can still cause nausea and dizziness at high doses, but nothing like the extreme nausea caused by GHB or it's prodrugs). I've had moments on GHB where I was so nauseated that I sort of wished I was dead, as if I ate a tin of chewing tobacco or something.

 

[3DQSAR]

https://sci-hub.st/10.1021/jm049762l

Slightly OT but 4 methylpregabalin is quite interesting. I imagine it's a bit of pain to make although I imagine that if the same resources were brought to bear on telescoping the synthesis, it's cost could drop to a level similar to the parent drug.

Long ago my doctor tried first gabapentin and then pregabalin for pain. Now both of them did help, but since I'm already a bit wobbly on my crutches, any medication that makes me even more wobbly is not ideal.

I am aware that there are some even more potent derivatives, but the synthesis of those (which contain strained rings) MUST be even more problematic and one cannot adapt the synthesis of the parent to make them.

The one thing I discovered was that pregablin (short term use) seems extremely effective in treating acute alcohol withdrawal. I've had friends try to use benzodiazepines without much benefit but were able to stop completely after consuming 30+ units of alcohol per day for years. To be clear, they REALLY wanted to stop but the physical stopped them.