Functional selectivity of GABA-B agonists

[polymath]

Not sure if this has been posted before, but it seems to explain why the effect of GHB is more pleasant and addictive than that of baclofen, despite both acting primarily on GABA-B receptors.

GABAB receptor allosteric modulators exhibit pathway‐dependent and species‐selective activity

Positive modulation of the receptor () represents a potentially useful therapeutic approach for the treatment of nicotine addiction. The positive allosteric modulators (s) of 39783 and 177 enhance ‐stimulated [[35] S] γS‐binding, ...

www.ncbi.nlm.nih.gov

Abstract

Positive modulation of the GABAB receptor (GABABR) represents a potentially useful therapeutic approach for the treatment of nicotine addiction. The positive allosteric modulators (PAMs) of GABABR GS39783 and BHF177 enhance GABA‐stimulated [35S]GTP γS‐binding, and have shown efficacy in a rodent nicotine self‐administration procedure reflecting aspects of nicotine dependence. Interestingly, the structural related analog, NVP998, had no effect on nicotine self‐administration in rats despite demonstrating similar pharmacokinetic properties. Extensive in vitro characterization of GS39783, BHF177, and NVP998 activity on GABABR‐regulated signaling events, including modulation of cAMP, intracellular calcium levels, and ERK activation, revealed that these structurally related molecules display distinct pathway‐specific signaling activities that correlate with the dissimilarities observed in rodent models and may be predictive of in vivo efficacy. Furthermore, these GABABR allosteric modulators exhibit species‐dependent activity. Collectively, these data will be useful in guiding the development of GABABR allosteric modulators that display optimal in vivo efficacy in a preclinical model of nicotine dependence, and will identify those that have the potential to lead to novel antismoking therapies.

 

[Nagelfar]

FWIW the GHB receptor (is it an orphan receptor?) has never been associated with the recreational value of the drug, has it? or is the GHB receptor now considered one of the GABA?(?) (I figured they were still distinct. Catch me up on that, if you may. Thanks)

 

[polymath]

FWIW the GHB receptor (is it an orphan receptor?) has never been associated with the recreational value of the drug, has it? or is the GHB receptor now considered one of the GABA?(?) (I figured they were still distinct. Catch me up on that, if you may. Thanks)

Yes. it's possible that the effect on GHB receptor is just an unwanted side-effect that is excitotoxic and can cause tremors/convulsions in overdose cases.

 

[Nagelfar]

Yes. it's possible that the effect on GHB receptor is just an unwanted side-effect that is excitotoxic and can cause tremors/convulsions in overdose cases.

So I note that, on the WP article for 'Gabazine', the alpha-4 beta-delta subunit in the GABA-a receptor is considered a functional part of the GHB receptor, might I construe it as, part of the scaffold complex of GABA-a, and antagonism itself might be the cause of the excitotoxicity?

 

[polymath]

^ Thanks for mentioning this, it may even mean that some other compounds binding to the "GHB receptor" could actually be full agonists at that GABA-A related site and be sedative without excitotoxicity.

 

[Nagelfar]

It would seem, if GHB is just a subsite / conformational peculiarity of the GABA a site, that might be the case. Receptor site complexes are interesting in that respect, and the semantics in research papers might often themselves be confused and too general in the criteria. e.g. one can always dig deeper / get more specific. One day types of agonism may have a plethora of terms according binding conformation and not simply agonist, antagonist, inverse agonist. That's why I am so interested in 'allosteric modulators' as that blanket term seems to imply this.

Have you looked up 'GABAa positive allosteric modulators' on WP?