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Kappa Opioid Antagonists

Gaz_hmmmm

Gaz_hmmmm

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Kappa Opioid Agonists

Anyone know of any?

I can only think of Salvia.

The reason I wish to know is cause:-

"For one of our three major endogenous opioid families is implicated in profoundly dysphoric psychological effects: a cruel negative-feedback system exists between the mu and kappa systems that "corrects" any "excess" tendency to well-being. Thus dynorphin activity at the kappa receptors tonically inhibits the release of dopamine from the mesolimbic terminals. If our well-being is to be sustainably enhanced, the balance between the two opposing opioid systems must be shifted."

^^ Taken from http://www.opioids.com/index.html

I was thinking if you take enough of a kappa opioid antagonist it should, in theory downregulate the kappa receptors, which would mean you could use mu agonists more so without getting withdrawl.

Anyone reckon this is possible? Say small doses of salvia, with an opi' afterwards?:\
 
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Asimadoline, dynorphin, Fedotozine are all kappa opioid agonists. I know that butorphanol (Turbogesic), which is used by vets is also a partial kappa opioid agonist.
 
I was under the impression that Ketamine, PCP and DXM (and dizocilipine) have all been found to be Kappa agonists.

The fact that Salvia and Butorphanol are both Kappa agonists as well may explain why they produce dissociative effects in many people.

I could be wrong though.
 
Cyclazocine is a mu antagonist and a kappa agonist. Acute administration is said to cause dysphoria and hallucinations, while prolonged administration has antidepressant effects and causes euphoria.
 
^ Sounds fun... or at least interesting. Any negative aspects (aside form the dysphoria), toxcicity, etc?
 
Kappa agonism seems to be something that has a lot of potential as an antidepressant therapy (there is a paper about salvia/salvinorin A having anti-depressant activity on Erowid). I can personally vouch that regular (2x a week), low sublingual doses of salvia tincture has an antidepressant activity
 
Oh F&B, I am pretty sure that kappa agonism is far from being a marker of dissociative action.

However, it does seem like there might be a "missing link" between Kappa agonism, NMDA antagonism and dissociative experience.

EDIT: Oh, another interesting thing: in my personal experience, daily sub-psychoactive doses of ketamine worked better for my depression than MAOis, and thats saying a lot for me..
 
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Another potent and selective synthetic kappa agonist I have in my files is called U50488. Unfortunately I dont suspect it is quite all that which is why you have never heard of it. It does supply a novel approach to alkaloid preparation though, since one uses the epoxide of cyclohexene as a starting material.

So for instance, one could react this with p-chlorophenyl-MgBr, convert the alcohol to a halide, then condense this with dimethylamine. I think there will be inversion in stereochemistry on reaction with SOCl2 or PBr3. Perhaps on condensing the amine there would be a second inversion and so a net retention of the trans configuration would be attained?!

I'd expect this 'candy to be active but is more the type of thing I would want to feed to kids than eat myself.
 

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I was more interested in whether or not you'd get even higher if you took a mu-agonist with a kappa-ANTagonist?
 
Yes, I've heard these anecdotal reports about salvia having antidepressant effects. When you say low, fnb, what kind of dose are you talking?
 
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