GS-39783 and other GABAb modulators

[ethacetin]

Wondering if anyone here has information about N,N'-Dicyclopentyl-2-(methylthio)-5-nitro-4,6-pyrimidinediamine, otherwise known as GS-39783.

It acts as a positive allosteric modulator for the GABAb receptor and has been shown to produce anxiolytic effects in animal studies, as well as reduce self-administration of ethanol, nicotine and cocaine.

Some of the reasons given in the abstracts I browsed through for looking into this and pharmacologically similar compounds were to better understand the role of GABAb in anxiety and depression and to hopefully develop new anxiolytics that didn't have the side effects associated with baclofen or benzodiazepines.

Other positive modulators of GABAb I found the most information on include CGP-7930, BHFF, BHF-177, and BSPP.

Does anyone know if there has been any talk of human trials on these compounds or promising new pharmaceuticals?

 

[serotonin2A]

The key thing here is that GS39783 is a PAM. The hope is that PAMs will have more "subtle" effects compared with orthosteric agonists. Similar strategies are being pursued for almost every receptor that is therapeutically relevant. I'm not sure if it will pan out but allosteric modulators theoretically could be very useful.

Seaside Therapeutics has a GABA-B agonist called STX209 that is in a clinical trial.

Addex has a GABA-B PAM called ADX71441 that is supposed to move to phase 1 testing but I'm not sure if trials have already started.

 

[ethacetin]

Thank you, I will look into those.

I hear what you're saying about PAMs. The thing is, benzodiazepines are PAMs for GABA-A, and they are one of my most favorite families of recreational substances (as well as hands down the most effective thing I've ever used to combat anxiety).
Furthermore, out of all the agonists for that receptor I've tried, GHB, Phenibut and even Baclofen were among my favorites there, leading me to hold the GABA-B subtype in high regard and think that we may just yet see some really awesome things come out of exploring it further.

So that was really my line of thinking here: If I like PAMs for GABA-A so much, and I tend to like agonists for GABA-B more than I like agonists for GABA-A, then perhaps I might end up really really liking PAMs for GABA-B

 

[serotonin2A]

Thank you, I will look into those.

I hear what you're saying about PAMs. The thing is, benzodiazepines are PAMs for GABA-A, and they are one of my most favorite families of recreational substances (as well as hands down the most effective thing I've ever used to combat anxiety).
Furthermore, out of all the agonists for that receptor I've tried, GHB, Phenibut and even Baclofen were among my favorites there, leading me to hold the GABA-B subtype in high regard and think that we may just yet see some really awesome things come out of exploring it further.

So that was really my line of thinking here: If I like PAMs for GABA-A so much, and I tend to like agonists for GABA-B more than I like agonists for GABA-A, then perhaps I might end up really really liking PAMs for GABA-B

If you think about how much an improvement benzodiazepines are over barbiturates then the reason for going in this direction makes a lot of sense.

It's interesting that you like GABA-B agonists so much, I haven't heard of many people that really like them. I suspect that if most people had to choose between baclofen and a benzodiazepine they would choose the latter.

 

[Morpheus19]

If you think about how much an improvement benzodiazepines are over barbiturates then the reason for going in this direction makes a lot of sense.

It's interesting that you like GABA-B agonists so much, I haven't heard of many people that really like them. I suspect that if most people had to choose between baclofen and a benzodiazepine they would choose the latter.

GBL/GHB is also a GABA-B agonist. And they are a lot of fun, for many people more so than benzodiazepines.

 

[serotonin2A]

GBL/GHB is also a GABA-B agonist. And they are a lot of fun, for many people more so than benzodiazepines.

That's certainly true about GHB, but it produces other effects that probably play a role in why people find it enjoyable. I don't see a lot of evidence that many people think baclofen is all that fun.

 

[endotropic]

That's certainly true about GHB, but it produces other effects that probably play a role in why people find it enjoyable. I don't see a lot of evidence that many people think baclofen is all that fun.

Probably not as fun as Gaba-a modulators for most people, but Baclofen reports on erowid frequently include the word "euphoria".

 

[serotonin2A]

Probably not as fun as Gaba-a modulators for most people, but Baclofen reports on erowid frequently include the word "euphoria".

I think that sampling suffers from a selection bias. There may be a small percentage of people who like baclofen, and it wouldn't suprise me if they take the time to write about it on erowid. But if you look almost everywhere else, most reviews I've read aren't positive.

One thing that leads me to believe that the people who find baclofen recreational may be responding to it a little differentially than the general population is that there have been so few reports of abuse. I cant think of another GABAergic medication that ended up being a drug of abuse where there were so many reports of people not enjoying the effects. With every example I can think of--diazepam, meprobamate, methaqualone, Soma, to name a few--you don't hear about many people who tried them and didn't like them. Another difference is that as far as I can tell most people who become dependent on baclofen (used for medicinal purposes) don't seem to be addicted to it.

 

[SONN]

I'm just gonna say that I hold GABA-b in high regard due to the fact that I love GHB and while phenibut is okay its totally not as cool as GHB. A human trial of these new ones would probably make me pretty excited lol Especially due to the fact that one essentially makes ethanol nicotine and cocaine less habit forming.

 

[sekio]

Part of the reason that GHB is so magic is because there is actually a specific GHB receptor which is excitatory rather than inhibitory like GABA-B, notably stuff like phenibut and baclofen are GABAB agonists but lack any affinity for GHBr.

 

[Erikmen]

Part of the reason that GHB is so magic is because there is actually a specific GHB receptor which is excitatory rather than inhibitory like GABA-B, notably stuff like phenibut and baclofen are GABAB agonists but lack any affinity for GHBr.

Interesting, although I don't really understand how.

 

[QuasiStoned]

Interesting, although I don't really understand how.

The GHB receptor was unknown until we found... well, GBH. GBH binds to the GABAb receptor and also to a novel receptor which has been named the GHB receptor. GBH receptor agonists are associated with stimulating effects. So any discussion of GHB has to take into account the GHB receptor.

 

[Hiltoniano]

What drugs other than GHB n GBL bind to the GHB receptor? What it be like combing a drug which purely acts on the GHB receptor with a purely GABAb agonist would it mimic GHB effects? Is that basically all that there is to the pharmacology behind the generally well liked effects of GHB consumption?? It's probably not that simple right?

 

[ethacetin]

OP here and the funniest thing happened, a couple weeks after making this thread a FOAF kicked us down a bottle of baclofen
My comments above were based on a handful of experiences from a number of years ago and I've had to re-evaluate much of this.

I was perhaps a bit careless when I stated GHB, Phenibut and Baclofen were among my favorite GABAergics, failing to mention that Methaqualone and Diazepam also rank among said favorites, and notably higher than Baclofen. But compared with the dozens of other GABAergics I have little to no interest in, that's still pretty high.

If I may posit a hypothetical metric, I would suggest there are different tiers of how awesome a drug is.
*At the top you have your drugs that are so fun and useful they have to be illegal (Heroin, Cocaine, Methaqualone, etc)
*Next you have drugs that are available by prescription but still fun enough for people to pay good money for them on the street (Percocet, Adderall, Valium, etc)
*Far below that is drugs that you'd still do if they were there and free but not many people really go out of their way for them

It's almost "apples and oranges" trying to compare a drug in one of those proposed tiers to any of the others.

Out of all the random stuff people got from their doctors and have given to me because they didn't want it, Baclofen is one of my favorites there.

And after a number of trials this past month (admittedly in the 100-200mg range, e.g. 10-20x what the doctor was calling a "dose") I have developed a new-found appreciation for it. The body buzz and effect on my mood and thought processes were quite pleasant, in a way I'm still having difficulties describing or even comparing to anything else I've taken.

But at the same time, if I had a bunch of money and was trying to get high there are many, many things I would seek to obtain before even considering Baclofen.
But then again, if it were a matter of simply walking down to the corner store and grabbing a quarter gram of Baclofen for the same price I can get a 6-pack of beer, 9 times out of 10 I'd be going for the Baclofen.

 

[ethacetin]

I perhaps also need to brush up on my pharmacology. Wikipedia is now listing barbiturates, benzodiazepines, thienodiazepines, ethanol, kavalactones, meprobamate, methaqualone, theanine, valerian, volatile/inhaled anesthetics and many others as PAMs, not agonists.

 

[ethacetin]

What drugs other than GHB n GBL bind to the GHB receptor?

1,4-butanediol, for one, which is a prodrug for GHB. In fact almost every GHBr agonist listed on the Wiki sekio linked is either a prodrug for GHB, a metabolite, or a structural analogue or isomer.

Now I'm curious what a GHBr agonist that had no affinity for GABA receptors would even feel like.

Trans-4-Hydroxycrotonic acid (T-HCA) is one such chemical, and is reported to "not produce sedation, and instead causes convulsions."

 

[ethacetin]

also, "administration of mixed GHB/GABAB receptor agonists along with a selective GABAB antagonist or selective agonists for the GHB receptor which are not agonists at GABAB, do not produce a sedative effect, instead causing a stimulant effect followed by convulsions at higher doses"

 

[ethacetin]

Either way, it seems that the GABA-B subtype simply hasn't been looked into to the extent that GABA-A has, and not as much is known about it or been developed to target it.
With many of the neurotransmitter/receptor systems in our bodies, there's generally a handful of really amazing drugs that display affinity for them and a ton of drugs that are just mildly okay or which don't even really produce much subjective effect at all.
I have a hunch that if humanity keeps probing we're eventually going to find substances selective for GABA-B that can hold their own against the heavyweights of the pharmacopeia.

 

[serotonin2A]

I perhaps also need to brush up on my pharmacology. Wikipedia is now listing barbiturates, benzodiazepines, thienodiazepines, ethanol, kavalactones, meprobamate, methaqualone, theanine, valerian, volatile/inhaled anesthetics and many others as PAMs, not agonists.

Many of them are PAMs. On the other hand, high concentrations of barbiturates can open the GABA-A channel on their own in the absence of GABA, which is one reason why they are more dangerous than benzodiazepines in overdose.

 

[Baclophiliac]

I think that sampling suffers from a selection bias...One thing that leads me to believe that the people who find baclofen recreational may be responding to it a little differentially than the general population is that there have been so few reports of abuse. I cant think of another GABAergic medication that ended up being a drug of abuse where there were so many reports of people not enjoying the effects.

Definetely agree with you on this one in respects to my individual experience. I was (and continue to be) prescribed baclofen for severe intercostal neuralgia this past December and could never had predicted the impact it had on my life. Baclofen is very much a dose dependent drug so I'll talk about the different "levels" I experienced over the next few months.

In the beginning I was prescribed two 10 mg doses a day. It would take about an 45 min to an hour to kick in much like most benzo's. I would then experience three hours of very mild anxiolytic effect followed by an exhaustion so intense I would have to go pass out for several hours. The sleep was the most restful I've had in my entire life. I noticed if I took under 5mg I would not experience this extreme somnolence (this will figure in later).

1 month later after consistently taking two 10mg doses daily:

One day I woke up and I just felt... Amazing. I suffer from daily panic attacks, moderate depression, and was using marijuana for at the time for medicinal purposes (ie the severe intercostal neuralgia + severe intestinal discomfort (diarrhea all day every day for 9 months caused my muscular spasms not allowing decal matter to pass through the intestines properly (however was previously using it recreationally daily before I got sick as well.)) I hadn't felt this relaxed and at ease for years. I tapered down to 2.5mg taken throughout the day every 23 minutes. The purpose of this downwards titration was to combat the somnelecence I had previously felt. At this level I experienced none of the sleepiness and in fact felt VERY energized throughout the day and found myself sleeping much less than before (10-12 hours daily down to 6to8). I started needing less and less marijuana to combat the pain (the effect was two fold-- not only was I in less pain because of the muscle relaxant effect I recieved significantly less reward from it ie less dopamine but also less crash. It also seemed to increase my pain tolerance as well) One day however I took a ten milligram pill out of curiosity to see if I would experience the same somnelecence I had before. Oh how wrong I was.

The next three hours was some of the best I've had in my life. The only other substance I can equate it to would be recreational use of amphetamines but also reminiscent of MDMA emotionally. I literally danced by myself in my living room for a good hour. Just how I mentioned earlier that there was a three hour period of mild anxiolytic effect and this too lasted for three hours followed by a crash I've only felt when coming off of SSRI's-- depression + crying etc. This lasted for the rest of the day and the entire next. After that experience I became aware that I would need to titrate up very slowly on this drug. As much fun as it was I didn't feel the urge to abuse it possibly due to the nature of this drug as an craving suppression agent. Not only did I feel no urge to relive that experience despite it seeming to be incredibly abusable I also felt very little urge to use any drug in a recreational sense.

I was was able to eventually continue my titration up after several weeks at 2.5mg and made my way up to 5mg every 40 min, then 10mg 1 hour, and then to 15 every 1h 20 min which is where I am at right now (100 mg daily). All the literature I've read seems to advise three daily doses but since I seem to be hyper sensitive I have erred on the side of caution so far and feel confident I can get there eventually. Throughout the titration process I had several side effects which seem to be entirely dose dependent. For instance around the 60mg daily phase I experienced restless legs nightly but once I got to 80mg this went away entirely. I also found myself sleeping only around 5 hours a night initially but this also faded and now I get 8-10 however always wake up at the 6 hour mark. The sleep is restful and within a few min of getting up i am fully awake. The last side effect was two fold-- insatiable sexual urges and a it became hard to ejaculate.

Originally I had attributed my extreme reaction to taking the 10mg to some sort of D/NE rebound which might have been part of it. It was at this point however that I remember a past drug side effect when I was on SSRI's. The side effect is not very common, but some people do experience sexual side effects (also why I think I'm one of the few people to have a very positive drug experience on baclofen) like I just mentioned on SSRI's and this led me to a few discoveries. Baclofens mechanism of action seems to reside in serotonin, norepinephrine, and dopamine (studies linked below). Then only reason I think this form of SSRI is treating me better than my past experience with them is the specific way it helps with serotonin (via 5htp) and the repression of glutamate. My theory is that while baclofen represses things like dopamine since its gabergenic I am also rebounding at a similar rate which is keeping me in a stable place but I'm sure there's more to it considering the effect on serotonin and norepinephrine.

This type of thing is way above my pay grade so I'd love to hear people's thoughts!

(additionally if I have used any terminology wrong my apologies I'm very new to this)

(I forgot to mention that now I am experiencing little no no anxiety like I had been previously. I haven't needed to take anti anxiety meds in months. My depression has also lifted and I am much more social/enjoying life like I haven't in years)

Serotonin
http://www.ncbi.nlm.nih.gov/pubmed/2562298

Norepinephrine
http://www.ncbi.nlm.nih.gov/pubmed/8057749

Dopamine
http://www.ncbi.nlm.nih.gov/pubmed/1684645