GABA Autoreceptor Antagonists ?!?!?!?!?!

[Charles Ferdinand]

I was thinking about psychopharmacology, and how amisuplride blocks autoreceptors at lower doses, so I said, can't the same be done with GABA?
a quick google lookup turned this:
http://informahealthcare.com/doi/abs/10.1517/13543776.2.11.1878?journalCode=etp

So is it possible or even feasible?

 

[sekio]

http://informahealthcare.com/doi/abs/10.1517/13543776.1.5.726

Here's one more.

 

[Epsilon Alpha]

I was thinking about psychopharmacology, and how amisuplride blocks autoreceptors at lower doses, so I said, can't the same be done with GABA?
a quick google lookup turned this:
http://informahealthcare.com/doi/abs/10.1517/13543776.2.11.1878?journalCode=etp

So is it possible or even feasible?

I am very interested to see where this goes, good find!
I'm extremely surprised by how simple the structures are though, I wonder if any close analogs are already in use for other purposes.

 

[raybeez]

I wrote this bit before realizing that we're talking about antagonists (not agonists!). I'll leave it up rather than delete because it explains why auto-receptor antagonists might be interesting:

Don't auto-receptors usually function in an inhibitory capacity? Presynaptic 5-HT1A autoreceptors inhibit synaptic serotonin release, and a2 autoreceptors inhibit NE release.

I've heard this used to explain why SSRIs/SNRIs increase suicidal ideation at the start of treatment (elevated pre-synaptic neurotransmitters causes an autoreceptor-mediated drop in synaptic neurotransmitters), and why they take 4-6 weeks before clinical effect is apparent (time frame corresponding to desensitization/downregulation of the autoreceptors)

I'm not sure if a pure antagonist would end up being useful. According to some models of depression/anxiety, overexpression/upregulation of autoreceptors is the culprit. Long term use of antagonists might cause autoreceptor upregulation causing some really long lasting discontinuation syndromes (but who knows if they'd be as bad as benzo/etoh/etc withdrawals).

In the case of SSRIs, pharma is examining using mixed SRIs/antagonists or partial agonists. The thought seems to be that this might lead to faster onset of clinical effects. Pindolol (5HT1A antagonist) has been added to SSRIs and shown to cause improved early responses, but no benefit after 4 weeks (fitting the theory above). Wikipedia mentions vilazodone and SB-649,915 as also being in the pipeline.

 

[Charles Ferdinand]

So GABA autoreceptors agonists would actually (and inmediatly) increase the GABA output?

 

[endotropic]

So GABA autoreceptors agonists would actually (and inmediatly) increase the GABA output?

I think you have it backwards, autoreceptor antagonists would increase GABA output acutely, while agonists would decrease output. From the link in your fist post:

"Compounds were tested for their ability to block agonist-induced inhibition of potassium-evoked GABA-release from rat cortex in vitro (a measure of GABA autoreceptor antagonism)"

Unpacking that part in bold a little bit, the agonist is inhibiting GABA release, through some potassium dependent mechanism, and their antagonist compounds block this inhibition.

 

[Charles Ferdinand]

You're right, absolutely right, my bad.
But back to the pharmacology: this could be promising compounds, and I'd love to try them, How come no one has thought of/tried to produce them before?