Some GABAb-related questions

[Limpet_Chicken]

Does anybody know anything about the activity of baclofen where the chloride is swapped out for either another halogen, a cyano group or a trifluoroalkyl? and what about the activity of the deschloro compound?

Also, how do the in vivo effects of agonists functionally selective for autoreceptors vs heteroreceptors differ?

Are any negative allosteric modulators known for GABAb receptors?

 

[Nexus298]

I was fascinated with this receptor after trying GHB, But after trying Phenibut and Baclofen and not getting much effect It leads me to believe that most of GHB's effect is from the GHB receptor. Is this whats happening or does GHB just have a better binding affinity?

 

[Limpet_Chicken]

Binding affinity doesn't say much, efficacy (or in the case of antagonists/inverse agonists IC:50), something can have a subnanomolar affinity for say, mu opioid receptors, but if it has crap all efficacy, it could merely be an incredibly potent, but worthlessly weak partial agonist, in fact very high affinity and little efficacy, yet remaining an agonist is likely to make for something quite unpleasant, especially in the case of GABAa or GABAb receptors, as its high affinity will lead it to displace GABA from the receptor if high enough and substitute it with itself, I.E worthless crap.

In the case of GABAa receptors for instance, that equals anxiogenesis, seizures, disinhibition of exitatory neurotransmission whilst simultaneously inhibiting inhibitory transmission.

Think barbs in reverse.

I am not sure about how much of GHBs effect is from the GHBr agonism though. I am on baclofen, although due to its impairing effect upon the memory, I do not regularly take it, and whilst it can be a little helpful for opioid withdrawal, or meh-ok-ish for my bad back, it is actually pretty shit as a recreational substance, one gets a relaxed feeling, with a strange sensation, like a drunkenness whilst having one's head immersed in fluid, almost.

But little aside from that and anxiolysis, or as a moderately effective sleep aid, its not up to much, I have tried phenibut, the subjective feeling of which is somewhat more enjoyable but again its bugger all special.

What I have noticed, is that both baclofen and phenibut take a very long time to come on, is this due to GABAb being metabotropic, or are they prodrugs? or what. Baclofen does nothing for me, even if plugged until perhaps 3.5 hours later, phenibut on the other hand, orally, I won't feel anything from it if I take it in the afternoon to afternoon-early evening the next day!

 

[Phener]

Does anybody know anything about the activity of baclofen where the chloride is swapped out for either another halogen, a cyano group or a trifluoroalkyl? and what about the activity of the deschloro compound?

No, but I would very much like to! Seems an obvious line of research (which surely would have been done when creating baclofen). Personally would just be very interested to see what happens when a bromine is added as this is a simple modification to a heavier atom. Akin to the difference between 2c-c and 2c-b. I would wonder if it increased or decreased GABAb agonism.

I was fascinated with this receptor after trying GHB, But after trying Phenibut and Baclofen and not getting much effect It leads me to believe that most of GHB's effect is from the GHB receptor. Is this whats happening or does GHB just have a better binding affinity?

I would imagine the GHB receptor does have a big influence in effects but personally found GHB less worthwhile medically and more recreational. The addiction and withdrawal was rather nasty and too problematic for regular use. (I know Xyrem is licensed but still personal opinion)

What I have noticed, is that both baclofen and phenibut take a very long time to come on, is this due to GABAb being metabotropic, or are they prodrugs? or what. Baclofen does nothing for me, even if plugged until perhaps 3.5 hours later, phenibut on the other hand, orally, I won't feel anything from it if I take it in the afternoon to afternoon-early evening the next day!

Agreed on that point, definately slow onset.

However I agree phenibut is more recreational or gives a more prominent buzz but to me it seems unclean and by that I mean less selective. There seems to be more going on with it that just GABAb agonism which is why I prefer baclofen. Both have there downsides though, withdrawal after prolonged use can be nasty.

GABAb agonism is the current line of research for stopping addictive behavior, following it very closely - hopefully within this decade more will come to light.

 

[Limpet_Chicken]

Shame it fucks up memory.

I want to know if antagonists (paradoxically GABAb antagonists possess antiseizure activity) can be safely taken without severe anxiogenesis, if the dose is carefully monitored, I believe they will be found to be nootropic.

Also, I want to know of any negative allosteric ligands.

 

[Phener]

Shame it fucks up memory.

I want to know if antagonists (paradoxically GABAb antagonists possess antiseizure activity) can be safely taken without severe anxiogenesis, if the dose is carefully monitored, I believe they will be found to be nootropic.

Also, I want to know of any negative allosteric ligands.

http://en.wikipedia.org/wiki/Saclofen

Well going on the WITHDRAWAL effects of baclofen I would predict that saclofen would be one NASTY compound to deal with.

 

[Limpet_Chicken]

Are there any partial antagonists/partial inverse agonists known for GABAb?

 

[seep]

LC, what effect are you after? There are no NAMs in the literature (so far as I can tell), but some of the PAMs have interesting properties and are quite labile insofar as what they're administered with or how much endogenous activity is present. There are also partial (orthosteric) agonists and I'm sure if you look into it enough, some of these partials will have inverse functionality.

Some of you baclofen fiends on this forum may be delighted to know that a baclofen prodrug is in trials:

1. J Pharmacol Exp Ther. 2009 Sep;330(3):911-21. Epub 2009 Jun 5.

Arbaclofen placarbil, a novel R-baclofen prodrug: improved absorption,
distribution, metabolism, and elimination properties compared with R-baclofen.

Lal R, Sukbuntherng J, Tai EH, Upadhyay S, Yao F, Warren MS, Luo W, Bu L, Nguyen
S, Zamora J, Peng G, Dias T, Bao Y, Ludwikow M, Phan T, Scheuerman RA, Yan H, Gao
M, Wu QQ, Annamalai T, Raillard SP, Koller K, Gallop MA, Cundy KC.

XenoPort, Inc., 3410 Central Expressway, Santa Clara, CA 95051, USA.
[email protected]

Baclofen is a racemic GABA(B) receptor agonist that has a number of significant
pharmacokinetic limitations, including a narrow window of absorption in the upper
small intestine and rapid clearance from the blood. Arbaclofen placarbil is a
novel transported prodrug of the pharmacologically active R-isomer of baclofen
designed to be absorbed throughout the intestine by both passive and active
mechanisms via the monocarboxylate type 1 transporter. Arbaclofen placarbil is
rapidly converted to R-baclofen in human and animal tissues in vitro. This
conversion seems to be primarily catalyzed in human tissues by human
carboxylesterase-2, a major carboxylesterase expressed at high levels in various
tissues including human intestinal cells. Arbaclofen placarbil was efficiently
absorbed and rapidly converted to R-baclofen after oral dosing in rats, dogs, and
monkeys. Exposure to R-baclofen was proportional to arbaclofen placarbil dose,
whereas exposure to intact prodrug was low. Arbaclofen placarbil demonstrated
enhanced colonic absorption, i.e., 5-fold higher R-baclofen exposure in rats and
12-fold higher in monkeys compared with intracolonic administration of
R-baclofen. Sustained release formulations of arbaclofen placarbil demonstrated
sustained R-baclofen exposure in dogs with bioavailability up to 68%. In clinical
use, arbaclofen placarbil may improve the treatment of patients with
gastroesophageal reflux disease, spasticity, and numerous other conditions by
prolonging exposure and decreasing the fluctuations in plasma levels of
R-baclofen.


PMID: 19502531 [PubMed - indexed for MEDLINE]

 

[Limpet_Chicken]

Curious to see if the effect I noticed upon early stage prodromal GHB/GBL withdrawal could be replicated.

Along with that sinking feeling that says 'oh shit, I've really fucking gone and done it aint I now?' where one realises what you did is going to bite you in the ass, and hard, I noticed a massive increase in ability to organise, systematise, order information etc.

I believe due to baclofen being a memory impairing drug due to decreased glutamate release, that it may be possible to have a non-neurotoxic (possibly, hopefully) moderate increase in glutamate release by taking a GABAb antagonist/negative modulator.

A weak partial competitive agonist might be safer, with a high enough affinity to displace GABA but low intrinsic efficacy enough to make it a weakish agonist at best, probably more pleasant than a full inverse agonist etc.

Similar things have been done at GABAa, mainly combining subunit selective antagonist/agonist combinations, such as alpha1/alpha5 selective antagonist/inverse agonists with alpha3 etc containing subunit selective agonist/partial agonist, to create a ligand which has enough agonistic activity to not be a convulsant, anxiogenic, all around hideous compound fit to be taken in vivo, and improve memory.

And as for the deschlorobaclofen question, I am simply curious what removal of that halide or substitution with other halides or pseudohalides does, I have access to shitloads of baclofen, grams of the stuff that I only very rarely ever take, and keep getting prescribed.

So anything doable in the way of experimenting, particularly nootropic focused is worth considering.

 

[amanitadine]

Strange, I have never noticed any real negative effect on memory with baclofen dosing. Quite the contrary actually, especially when I am on the downslide, which I believe is similar to what you experienced on the eve of GBL withdrawal. I have a flow of information and ideas that comes forth quite naturally, and even enjoy hearing myself think out loud, much to the chagrin of those around me ;D And deschlorobaclofen....you mean phenibut? Call me stupid but...err just call me stupid. I've looked around for info on other halo subs but didnt come across anything. I admittedly didnt look too hard...prolly enjoying listening to myself think out loud too much at the time....

and thanks seep for the info on arbaclofen placarbil. Nice idea.....but the name sounds like its inventor was busy gurgling cum at the moment of creation. :D

 

[Limpet_Chicken]

Hm, oops, of course, its phenibut.

What about other substituents other than (pseudo)halides? alkyl, olefin, alkynyl, alkoxy, alkyl ester, primary/sec/tert amine/amides etc? that chloride could be swapped out for something like that via nucleophillic substitution pretty easily, although it is a pretty shitty leaving group, yield isn't really important I guess, if one is merely curious.

 

[seep]

In GABAb receptor panels, after desensitization is brought about by GABA bombardment:

• Partial agonists become silent antagonists.
• Silent antagonists become inverse agonists.
• Allosteric modulators are potentiated.

Source:

NSFW:

1. Eur J Pharmacol. 2009 Jan 28;603(1-3):37-41. Epub 2008 Dec 16.

Changes in the properties of allosteric and orthosteric GABAB receptor ligands
after a continuous, desensitizing agonist pretreatment.

Gjoni T, Urwyler S.

Novartis Institutes for BioMedical Research, Neuroscience, Basel, Switzerland.

It has been estimated that only 15% of the compounds classified as silent G
protein-coupled receptor antagonists are indeed devoid of either positive or
negative intrinsic efficacy. Considering that 40% of all drugs on the market
target G protein-coupled receptors mainly as orthosteric ligands, elucidating
their intrinsic properties is becoming increasingly important. While agonism can
be demonstrated using appropriately sensitive experimental setups, the detection
of inverse agonism can be limited by a low degree of constitutive activity in
many assay systems. In this study, changes in ligand behavior upon a lasting
pretreatment with gamma-aminobutyric acid (GABA), that induced receptor
desensitization, were observed, measuring the second messenger cyclic AMP (cAMP)
in a GABA(B) receptor-expressing recombinant cell line. The GABA(B) receptor
partial agonist 2-OH-saclofen lost its ability to inhibit 7beta-forskolin-induced
cAMP production upon GABA-pretreatment. The "silent" receptor antagonists
CGP62349, CGP52432, CGP56999 and SCH50911, on the other hand, stimulated
7beta-forskolin-induced cAMP production under these conditions. The inverse
agonism of CGP56999 was inhibited by the efficacy-deficient 2-OH-saclofen,
proving it was truly mediated through the orthosteric site of the GABA(B)
receptor. Finally, the positive allosteric modulator GS39783, which previously
only marginally inhibited cAMP production, suppressed it by 60% both alone and in
the presence of the competitive receptor antagonist 2-OH-saclofen, thus GS39783
became an allosteric receptor agonist at desensitized GABA(B) receptors. These
changes likely reflect adaptations in the mechanisms of GABA(B) receptor function
following desensitization and may be important in the elucidation of intrinsic
ligand efficacies as well as for the consequences of continuous drug treatment.


PMID: 19109945 [PubMed - indexed for MEDLINE]

GPCR integrity is crucial to neural functioning, but GPCRs are so very fragile that it almost seems that this fragility also has a regulatory function.