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Might the glycine receptor have allosteric binding sites similar to GABAA?

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seep

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Note: This post is about the glycine-regulated chloride channel, not the glycine binding site on NMDA receptors


Might the glycine receptor have an allosteric binding site similar in function to the bezodiazepine site on GABAA?

Both receptors are ligand-gated chloride channels. They both serve in an inhibitory capacity in the CNS. They are both widely distributed. They are both pentamers. Their active sites both have endogenous ligands that don't do a hell of a lot by themselves.

It seems GABAA is the target of so many pharmaceuticals because Leo Sternbach (discoverer of benzodiazepines) got lucky and found the GABA molecule a buddy.

I take it we still don't know much about the glycine receptor, but suppose for a second that we found a way to dramatically increase its opening frequency, causing significant chloride influxes to the respective neurons and shunting the relevant pathways. (What might that feel like?)

A quick glance at known glycine receptor agonists leaves one underwhelmed. Wiki lists the amino acids alanine, dimethylglycine, glycine, hypotaurine, methylglycine, serine, taurine, trimethylglycine. One gets the sense that not much headway has been made toward designing high-efficacy glycine agonists.

But then one looks at one of the known antagonists of the glycine receptor: Pitrazepin:

220px-Pitrazepin-ifa.png


It is also known that pitrazepine has affinity for the benzodiazepine site on GABAA (where it acts as a weak antagonist). And so--one surmises--it is also a negative allosteric modulator at the glycine receptor (i.e. it does not dock onto the same site as the glycine molecule).

One therefore ponders if there is a pharmacophore for positive allosteric modulation of the glycine receptor . . .

Thanx in advance for any info!
 
RECEPTOR SELECTIVE AGONISTS
Glycine (G 7126)
β-Alanine (A 7752)
Taurine (T 0625)
RECEPTOR SELECTIVE ANTAGONISTS
Strychnine (S 8753)
Caffeine
PMBA (P-204)
Cyanotriphenylborate
5,7-Dichloro-4-hydroxyquinoline-3-carboxylic acid

I feel as if glycine receptor antagonists might be more... useful(compared to agonists). my reasoning is because look at two main antagonists, caffeine and Strychnine and how useable they are..
 
Yeah, for poisoning people.

I believe GlyR agonists are likely not to be recreational, but possibly make excellent muscle relaxants, or paralysing agents.

Most glycine receptors are expressed in the spinal cord and brainstem, and appear to control muscular excitability and tone, a mutation in glycine transporters (I think it is transporters, it was a while since I read about it) causes 'stiff person syndrome' which causes severe tonic muscle spasticity and immobility, and tetanus toxin, produced by Clostridium Tetani acts analogously to the way botulin works on nicotinic acetylcholine receptors, preventing presynaptic release from vesicles into the synaptic cleft, and in the case of tetanus, its pretty well known what happens to you.

GlyRs form pentamers, or at least to my knowledge the alpha subunits do, there are alpha subunits 1-4 and a single beta subunit, expression appears to change shortly after birth, I assume in all mammals, but at least in the rat, and mouse, neonates show expression almost entirely of alpha2 subunit containing receptors, which are not totally, but largely insensitive to strychnine, this changes to the strychnine-sensitive receptor types after around 14 days post birth.

I have read sources which speculate that central GlyRs might be involved in directing evolution of cortical morphology in the developing organism, as well as regulating response to mechanical stimulation and movement.

The adult form at least, has at the minimum two binding sites, that I know of, one recognizing agonists and the other antagonists, although IIRC I have seen strychnine and tutin (the convulsant toxin present in Coraria Thymifolia, and related Coraria species, and is occasionally responsible for outbreaks of highly toxic honey when the nectar is eaten by bees, or honeydew from insects is fed on and turned to honey) referred to as competitive antagonists, which implies that either the antagonist binding site is the orthosteric site for the endogenous agonist, or that there are both orthosteric binding site(s) for the endogenous agonist and an allosteric positive modulator site, although I am not 100% sure which.

There appear to be two modulatory sites binding cations, one binding divalent anions, such as zinc, Ca++, Pb and La, and possibly a further cation binding site, also CsCl acts as an agonist of GlyRs (affinity I do not know) in a strychnine-sensitive manner, addition of strychnine abolishes agonist activity of CsCl, counterion is important also.

Seemingly lower concentrations of divalent ions enhance strychnine binding, whereas higher levels of the same decrease it.

Glycine itself reduces pressure induced and neuropathic pain in the rat, whilst strychnine increases neuropathic pain (I am sure you would feel extra shitty if somebody was trying to break your fingers AND pump you full of strychnine at the same time, jesus, the things they do to lab animals sometimes is fucking disgusting, I couldn't do that sort of work, I would go home every night feeling dirty and soiled with what I had done in the name of progress and torn to shreds by guilt, I really don't understand how people can do it :/)

As for high affinity agonists, gelsemine, from the toxic plant Gelsemium Sempervirens is a reasonably potent glycine agonist with a Ki value of 18uM, picolinic acid is an agonist with micromolar affinity, as is 6-aminonicotinic acid.

There is a high homology between GABAaRs and GlyRs, and many antagonists such as picrotoxinin and bicuculline show some crossover, and IIRC the barbs, and some benzos, flunitrazepam having amongst the highest affinity (around 9uM) as agonists)
 
Thanks for the detailed response. I know the glycine receptor is most famous for its role in the spine and medulla, but isn't it also distributed in (for lack of an appropriate term) the mental neighborhoods? If not, how then is caffeine a psychostimulant?

I've taken megadoses of taurine while on a cycle of I forget which anabolic steroid and besides helping with the spastic lumbar pain, it seemed to be intensely calming and devoid of ataxia (therefore maybe not a muscle relaxant in the familiar sense?). I've tried to reproduce the taurine experience in the absence of lumbar spasms but have been unsuccessful.

I think strychnine binds to the same site as glycine but can't remember why I think this. Also, gelsemine is a convulsant and so a glycine receptor antagonist.

Is picolinic acid centrally active?

Cesium chloride: wow.
 
Limpet_Chicken said:
...a mutation in glycine transporters (I think it is transporters, it was a while since I read about it) causes 'stiff person syndrome' which causes severe tonic muscle spasticity and immobility...
Click to expand...

A bit off-topic, but I wonder if we know of the consequences of sub-acute but still measurably overactive glycine transporters. Would this have a simultaneous dulling and pro-convulsive effect (dulling because of the lack of glycine for NMDA receptors and pro-convulsive because of the lack of activity at the glycine chloride channel)? That could get really ugly over a period of time...
 
I was under the impression gelsemine was definately an agonist, it appears to act as a paralysing agent in large doses and a powerful muscle relaxant in smaller ones, fatal overdoses cause ptosis and my herbal that references it 'a modern herbal' author unknown, front pages are missing, lists it as 'a powerful spinal depressant'

So most definately an agonist, and quite in opposition to the action of strychnine, for which it is listed as a specific antidote (and vice versa)

I wonder, looks like an interesting compound. I might just have to look for live Gelsemium plants.
 
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