Binding Affinities and Receptor Displacement of GABAergic Compounds

[IndigoDahli]

Hey there. I have been doing some extensive research on the mechanisms of action of Lorazepam, Pregabalin, and Gabapentin. Also, incorporating Kava Kava into my daily therapeutic regimen. I wanted the communities insight in how to maximize the effect of each of these compounds (Kava Kava having multiple psychoactive compounds).

I know that Pregabalin will displace Gabapentin at the Alpha 2 Delta protein (the auxiliary sub-unit that modulates voltage-gated calcium channels). Will any Gabapentin still be active or does the Pregabalin completely displace the Gabapentin? Will Lorazepam displace Pregabalin? or since Lorazepam binds to the Benzodiazepine site and modulates the GABA type A receptor (GABAA), that Lorazepam and Pregabalin can be taken in conjunction with one another without any binding issues or possible receptor displacement?

Also, would staggering Gabapentin doses AFTER ingesting Pregabalin increase the effect on the Alpha 2 Delta protein? Or would the Pregabalin binding affinity be so much higher, rendering any further Gabapentin dosing ineffective?

Also, how would the multiple psychoactive compounds of Kava Kava (some GABAergic) influence Lorazepam, Pregabalin, and Gabapentin? Would there be any binding or displacement issues combining Lorazepam, Pregabalin, and Gabapentin with any of the Kavalactones?

-Indigo

 

[Pomzazed]

Gabapentoids (gbp, pgn) binds at different site so it would not displace/get displaced by benzodiazepines (lorazepam)

Other questions are of interested to me too, esp the displacements between gbp and pgn

 

[sekio]

Pregabalin and gabapentin don't bind at GABA_A/GABA_B despite their names. Lorazepam doesn't compete with pregabalin or gabapentin for binding.

Because any one drug is unlikely to bind to 100% of receptors I'd expect that gabapentin and pregabalin could be taken together for a synergistic effect, I don't think that one would block the effects of the other.

Kavalactones seem to have widely differing pharmacology, some are GABA_A positive allosteric modulators, some bind at CB₁ as agonists, some are MAO-B inhibitors, and some also act at L-type calcium channels or sodium channels of varying sorts. In addition they act as liver enzyme inducers, notably CYP1A1 which may or may not increase the toxicity of polycyclic aromatic hydrocarbons such as benzo[a]pyrene (found in combustion products/tars).

 

[Cotcha Yankinov]

I know that Pregabalin will displace Gabapentin at the Alpha 2 Delta protein. Will any Gabapentin still be active or does the Pregabalin completely displace the Gabapentin?

IIRC it might just be that pregabalin has much better pharmacokinetic factors and pregabalin's affinity for alpha2delta may be similar to gabapentin's, I can't quite remember. But you would have to take into account that gabapentin may saturate the amino acid transporter thing that helps absorb it, independent of competitive interactions at alpha2delta itself.

I assume there would only be a synergystic effect at alpha2delta itself. Ligands don't necessary knock each other off of receptors/channels, they just bind when the receptor is free. And with antagonists, its not like a scenario where a weak partial agonist is displacing a strong full agonist (which could result in a decrease in the actions of the full agonist).

If pregablin has a really fast "on rate" and slow "off rate" on the receptor compared to gabapentin then the gabapentin may not have many opportunities to bind and some of it may essentially be wasted.

 

[AlphaMethylPhenyl]

Pregabalin and gabapentin don't bind at GABA_A/GABA_B despite their names.

some bind at CB₁ as agonist CYP1A1 which may or may not increase the toxicity of polycyclic aromatic hydrocarbons such as benzo[a]pyrene (found in combustion products/tars).

1. If I remember, there is literature that connects gab/preg with GABAergic activity, but not as a direct effect.

2. More importantly, the nebulous study out of Italy that cornered yangonin as a CB1 ligand is the only known such study target. As such, it may be impossible to duplicate (remember the tramadol in plant study?). If it is a substrate, it could have a very low efficacy/affinity so as to be almost inactive. It could be an inverse agonist, silent antagonist, barely a partial (e.g. abilify). So basically can you pull up another source on Kava and CB1 that validates your statement? There may be one, I may just be unaware, though I usually keep up with the literature, and this would be a big finding.

 

[asecin]

Pregabalin and gabapentin don't bind at GABA_A/GABA_B despite their names. Lorazepam doesn't compete with pregabalin or gabapentin for binding.

Because any one drug is unlikely to bind to 100% of receptors I'd expect that gabapentin and pregabalin could be taken together for a synergistic effect, I don't think that one would block the effects of the other.

Kavalactones seem to have widely differing pharmacology, some are GABA_A positive allosteric modulators, some bind at CB₁ as agonists, some are MAO-B inhibitors, and some also act at L-type calcium channels or sodium channels of varying sorts. In addition they act as liver enzyme inducers, notably CYP1A1 which may or may not increase the toxicity of polycyclic aromatic hydrocarbons such as benzo[a]pyrene (found in combustion products/tars).

i took kava with alcohol regularly for a while and i had elevated liver enzymes which alcohol or kava alone didnt do in the past. im pretty sure kava interacts with a lot of stuff, not just alcohol. im curious as to what other things to be careful with when trying kava? is half life really long? i wouldnt wanna mix it with other things like pills besides alcohol, seems serious. it kind of reminds me of how dangerous kratom was when combined with alcohol and various pills. the half life of its bioactives were like 2-3 days!

 

[sekio]

If it's this article you got the kratom half life from, the data they presented suggests the actual half life is something around 2 hours, there was one person in the study who must have lacked the proper liver enzymes that had an abnormally slow metabolism of the mitragynine and that case was a t1/2 of 24 hours. Kratom is actually pretty safe on its own.

Kava I cannot say the same for, there are not a lot of published studies on the exact mixture of kavalactones so it's hard to say the prevalence of known toxic compounds (yangonin, methysticin, dihydromethysticin). But those compounds are either direct promoters of cell death or they induce liver enzymes that increase production of toxic metabolites (of polycyclic aromatic hydrocarbons).

 

[asecin]

there are a lot of deaths contributed to kratom as FDA started investigating. they released report this year and are trying to ban it, again. im not sure how many of the deaths were related to mixing it with other drugs though, thats not very clear. i, for certain can state that i developed hepatitis from mixing it with alcohol. by itself, there are several reports of salmonella, so even then its not completely safe. im still looking up to kava as alternative, but i wouldnt mix it with alcohol

http://www.foodsafetynews.com/2018/02/fda-says-44-deaths-linked-to-kratom-products-recall-initiated/
http://www.foodsafetynews.com/2018/02/kratom-linked-to-salmonella-outbreak-cdc-posts-warning/

 

[sekio]

Most of the kratom toxicity reports I have seen are in combination with other drugs. And certainly Salmonella would be the result of contaminated plant material; it's not a drug-induced effect.

 

[AlphaMethylPhenyl]

Kava I cannot say the same for, there are not a lot of published studies on the exact mixture of kavalactones so it's hard to say the prevalence of known toxic compounds (yangonin, methysticin, dihydromethysticin). But those compounds are either direct promoters of cell death or they induce liver enzymes that increase production of toxic metabolites (of polycyclic aromatic hydrocarbons).

Do you know what part of the CNS/brain these "toxic compounds" act on? Also was it specific as to apoptosis or necrosis in the literature? Guessing the latter, maybe it's implied, I'm a newb. I mean, don't all GABAergics facilitate synaptic pruning? Also, synaptic pruning goes on until age ~26, right? Perhaps it's just continuing that process, making room for further dentritic branching, which is in essence adaption, as its connections rather than aggregate neurons that really matter.

I could be way off here. Just thinking.

This is the first I'd heard of Kava having this sort of effect.

 

[Limpet_Chicken]

Its hepatotoxicity rather than a neurotoxic effect with kava, the primary sources being poor-quality material which included the areal
portions of the plant, such as stem cuttings/peelings as well as the root.

Also there is a division in the classification of kava cultivars into 'noble' and 'non-noble' varieties, the latter being most commonly, the 'tudei' varieties, which in native use are never used on a regular basis, although IIRC are sometimes used for ceremonial occasions. The noble varieties contain much lower contents of the toxic compounds compared with nontoxic kavalactones, whilst the non-noble contain more of the nastier kavalactones along with the toxic alkaloids such as pipermethystine and the chalcone flavokavain B, again known to be toxic, not sure whether the other related chalcones flavokavain A and flavokavain C are similarly hepatotoxic, but if using kava then the tudei varieties ought to be avoided, and the noble varieties only used, and to avoid poor-quality cheapo stuff lest it contain the above-ground nasty crap present there.