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Selective NE receptor antagonists? (+DAT ligands?)

Nagelfar

Nagelfar

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Are there any NE receptor antagonists that leave dopamine receptors much less affected? I was thinking a DRI that also acted as a specific antagonist for NE (blocking both DA uptake and NE receptor activation) would be very abuseable, seeing as the NE to DA ratio seems to have to do with likeability.

Though, just the existence of a fairly selective NE antagonist would seemingly have potential for the best potentiator of dopaminergics.
 
Nagelfar said:
Are there any NE receptor antagonists that leave dopamine receptors much less affected? I was thinking a DRI that also acted as a specific antagonist for NE (blocking both DA uptake and NE receptor activation) would be very abuseable, seeing as the NE to DA ratio seems to have to do with likeability.

Though, just the existence of a fairly selective NE antagonist would seemingly have potential for the best potentiator of dopaminergics.
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There are at least five kinds of NE receptors (two alpha subtypes and three beta subtypes). Which one of them do you want to block?

Drugs like clonidine decrease NE activity by acting as agonists in the presynaptic alpha2 receptors that inhibit NE release.
 
polymath said:
There are at least five kinds of NE receptors (two alpha subtypes and three beta subtypes). Which one of them do you want to block?

Drugs like clonidine decrease NE activity by acting as agonists in the presynaptic alpha2 receptors that inhibit NE release.
Click to expand...

From literature I've read, I am assuming Alpha blocker would be the more viable of the two, as beta without it is frequently cited as dangerous in such cases.

My question is firstly whether there are selective blockers for NA over other monoamines in currency with good efficacy, used in the medical &/or academic RC capacity, regardless of sub-type specificity, as dopamine-drug potentiators (as unselective as possible seems safest)? Is this truly viable with alpha &/or beta blockers? It is only a secondary consideration about which sub-types are easier to single out for this effect and which may be the best for dopamine's euphorigenic potentiation. Theoretically of course, as there is not to my knowledge a pool of practical application for much of a concrete basis on such experiences used in large amounts with DAT uptake inhibitors. (though if extant, would be just as fascinating related here in this regard)

Would there, for instance, be a safe ratio at which a DRI was also an alpha or beta blocker due to, as far as I know, NE also being transported when in large amounts by DAT which may off-set or mediate the effect of NE. From what I understand, an unselective as possible NE antagonist (alpha & beta) would be safest; if a drug were a certain affinity for DAT, it could be a certain affinity as an unselective NE antagonist that may be purely euphorigenic?

Perhaps NE release blockers are a better candidate? (e.g. Bethanidine, Bretylium, Guanadrel) Would their effects be mutually exclusive with monoamine reuptake inhibiting ligands on a transporter by transporter basis if occupied with a DRI?
 
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Labetalol is one compound that blocks both alpha and beta adrenergic receptors. One of its uses is as an antidote for the peripheral sympathomimetic effects(hypertension, tachycardia, etc.) in stimulant overdose. I don't know if it crosses the blood-brain barrier, though.

Most alpha or beta blockers have no affinity for DA receptors, so one doesn't have to worry about DA antagonism.

I'd just try taking some clonidine with speed and see whether it makes the experience more pleasant. I don't think it works, though, clonidine alone causes dysphoria in some people.
 
polymath said:
I'd just try taking some clonidine with speed and see whether it makes the experience more pleasant. I don't think it works, though, clonidine alone causes dysphoria in some people.
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Clonidine is an agonist though, not an antagonist. My thinking was based upon the theory of less NE affinity and more DA affinity being the cause for greater reinforcement among dopaminergic drugs.
 
Clonidine is an agonist at the presynaptic alpha2 receptors. That produces an effect that is opposite to the activation of postsynaptic NE receptors... Also, yohimbine, an alpha2 antagonist, is a stimulant.
 
polymath said:
Clonidine is an agonist at the presynaptic alpha2 receptors. That produces an effect that is opposite to the activation of postsynaptic NE receptors... Also, yohimbine, an alpha2 antagonist, is a stimulant.
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That is remarkable. What is the mechanism for clonidine to agonize presynaptic but not be transported to areas of the postsynaptic once passed the BBB then, if you know? I'd be interested to know if cocaine worked the same way on dopamine receptors of the same subtype in different areas: I have read that cocaine binds to certain proteins that may herd its transport to certain areas of the brain, maybe it's fair to speculate that possibly it is transported by such proteins more thoroughly to the nucleus accumbens than some other areas moreso than some other stimulants.
 
Clonidine antagonizes only presynaptic receptors because the a2 receptor is primarily a presynaptic receptor. It is not that it is physically isolated from postsynaptic a2 receptors so much as that a2 receptors function specifically to monitor NE concentrations in the synapse and adjust NE release through negative feedback.
 
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