Research directions - the anxiolytic effect

[headsup]

I thought it would be a good idea to have a thread where people can contribute -

A. What they know about new/novel anxiolytics, and
B. The actual mechanism of anxiety, and how this might relate to developing new types of anxiolytics

I'm only really aware of the GABA-A stuff - isolating the receptor subunit responsible for the anxiolytic effect and finding a drug selective to that.

BilZ0r expressed the limiting case for this line of research very simply and clearly in the 'other' GABA thread (which is about the hypnotic effect, hence this thread) -

The problem lies in, as I said, that a particular kind of GABA-A receptor complex needs to be expressed in a particular area of the brain, and that area needs to be responsible for the particular function. Then it's just up to medicinal chemists to find a selective ligand.

If on the the other hand, the area in question has many kinds of GABA-A receptor complexes, and those complexes are expressed in other parts of the brain, then a selective drug can not be made.

To me this strongly implies that we'll no doubt see GABA drugs with an improved anxiolytic to side-effect ratio, but probably never the 'perfect' anti-anxiety version that people want.

So with this perfect anti-anxiety drug in mind, I wonder other promising research directions exist?

 

[headsup]

BTW I mostly lurk, sorry about the lack of an intro

 

[headsup]

Poking about for better GABA type anxiolytics, I came across this

"Modifying quinolone antibiotics yields new anxiolytics"

which basically claims to have found a compound that is alpha-2 subtype selective (ie anxiolytic according to BilZ0r's chart) and that acts on a specific site.

Interesting?

 

[fastandbulbous]

The quinolone antibiotic mentioned seems to have the anthranilic acid structure in common with methaqualone (structure in red - see attached jpeg). Does anyone know of any other anxiolytics with this structure in common (other than obvious methaqualone analogues like mecloqualone)

 

[BilZ0r]

Well some people say that anything which is amnesic should be anxyiolytic... scopolamine is good at making you forget things...

I think a highly centrally active alpha-2 agonist should be good too... decreasing Noradrenaline release...

Buprenorphin should be quite good for panic, not really anxiety per se though. That is, if you believe anxiety and panic have completely different neural substrates, which I think they do.

As far as the mechanism of anxiety, it kinda splits... there is probably normal, physiological, anxiety... the kinda shit that you get when you've done something stupid... Conversly, you're going to have patho-physiological anxiety, aka anxiety disorders. What mediates normal anxiety is going to be relatively different to the problematic form.

As far as the mechanism goes, it's something that people really haven't touched on that much... the problem is, you've got cognitive scientists... and neurophysiologist, and they don't really like each other most of them time... and so things haven't really come to head as far as many tests of the theories proposed by cognitive scientists.

 

[headsup]

I think a highly centrally active alpha-2 agonist should be good too... decreasing Noradrenaline release...

is alpha-2 associated with modulating noradrenaline alone then?

 

[BilZ0r]

Probably not... I'd geuss it decreases serotonin and dopamine too... probably a bucnh of neuromodulators.... all of those presynaptic inhibitory like receptors... e.g. 5-HT1A, H3, alpha2 CB1, tend to inhibit the shit out of monoamine release....