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D1 selective agonists

polymath

polymath

Bluelight Crew
Joined
Nov 4, 2010
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Hello,

found this some time ago: https://en.wikipedia.org/wiki/SKF-81,297

SKF-81,297 is a synthetic drug of the benzazepine chemical class that acts as a selective dopamine D1/D5 receptor full agonist, and produces a characteristic stimulant-like pattern of anorexia, hyperactivity and self-administration in animals.[1] This profile is shared with several related drugs such as 6-Br-APB and SKF-82,958,[2] but not with certain other D1 full agonists such as A-77,636, reflecting functional selectivity of D1 activation.[3][4][5] Newer findings reveal that SKF-81,297 additionally acts as a partial agonist at D1-D2 receptor heteromers.[6]
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Seeing from this that selective direct dopamine agonists can have a psychostimulant effect like amphetamine, I got the idea that maybe a D1 selective partial agonist could be like "buprenorphine of stimulants", which would simply stop having effect if abused, instead of making you able to stay awake for a week and end up in the psych ward...

A plant alkaloid stepholidine is thought to be a D1 partial agonist and D2 full antagonist, and seems to have some anti-addictive effects. See the link below.

https://www.ncbi.nlm.nih.gov/pubmed/24145772

There's some problems with this though - some paper claimed that stepholidine is actually a full antagonist at D1 too. Also, some D1 agonists seem to act through a different secondary messenger than SKF-81,297 and not produce a stimulant effect (similarly like some 5HT2A agonists are not hallucinogenic).

What do you think would happen if someone ingested aripiprazole (which blocks D2 and D3 receptors but leaves D1 free) and then took a non-specific dopamine enhancer like L-DOPA on top of that? Could the combination act like a selective D1 agonist? Of course this is not a valid reason to take an antipsychotic unless you already know for certain that they don't cause akathisia/dyskinesias/MNS to you, and the L-DOPA can also cause peripheral side effects because it's also converted to dopamine and norepinephrine outside the CNS, so don't take this idea too seriously. :D
 
Tbe L-DOPA idea would only work if (theoretically of course) a combination with a DOPA-decarboxylase inhibitor were used, and it be limited to the periphery, ala say use of hyoscine butylbromide to counter fly agaric nausea if any when using them.

There is one issue with dopamine agonists, although never taken a super-selective one, is that they need some titrating up, I've tried piribedil (pass on that one, I don't like adrenergic autoreceptor antagonists one bit) and am on pramipexole.) It isn't a psych ward its likely to send you to, its a toilet bowl=D

Exorcist esque pukefest if you get that one wrong and titrate too fast.
 
pramipexole low doses is super nice with long acting opioids,but you need to know your dosages,expecially with opiates that can also provoke nausea
 
I was under the impression that limbic tract was basically unconditionally firing if the cortex did. This is why we feel good when we critically think. Am i off here?
 
Ho-Chi-Minh said:
I was under the impression that limbic tract was basically unconditionally firing if the cortex did. This is why we feel good when we critically think. Am i off here?
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I believe there was originally some argument as to whether or not the prefrontal cortex was continuous or separate with the "limbic system" because the connections are so strong. I'll bet there are some people who consider the PFC part of the limbic system. The ventral prefrontal cortex in particular plays a critical role in our emotions.

CY
 
I guess the prefrontal cortex comments above were intended to that other thread...

On the actual subject, it's true that you don't necessarily know from lab experiments whether some compound causes nausea as a side effect, because some species (most notably rats) don't even have a neural mechanism for feeling nauseous. I wasn't thinking about this when posting this thread.

The idea of making a nonselective compound "better" by blocking some of the targets it affects was probably first used when pentazocine was used as an opioid with tripelennamine (which is supposed to block kappa receptors, making the effect of the former compound more euphoric). One example I can think of is making the effect of some crappy stimulant like propylhexedrine or phentermine better by taking it with a norepinephrine reuptake enhancer (are there any known chemicals with that effect?)
 
Thanks for the links, LC. Maybe there's some natural compound selective for NET, too.
 
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