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Selective Dopamine Releasing Agents ?

MedicinalUser247

MedicinalUser247

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I was just wondering about something. Does anyone know if SDRA's exist ? Or what comes closest to a SDRA with no effect on Norepinephrine ? I'd love to read about it if anyone has any information on it. Thanks.

p.s. I only want information Dopamine only. Thanks.
 
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Unfortunately there doesnt seem to be any DRAs purely selective for dopamine. Wikipedia lists cis-4-MAR as one of the most dopamine selective stimulants but that still releases NET.

2-FluoroMethCathinone and 3-Methoxy-Methcathinone are also listed as more selective for dopamine compared to most other stims but due to the similarity of DAT and NET transporters its unlikely to get that to work 😕

There are some selective DRIs though like amfonelic acid or some of the RTI analogues but as far as releasing agents go it doesnt seem to exist as of now. I wonder if some of the SDRA tryptamines could be modified to be more selective for dopamine and less for serotonin though. Might be the best bet outside of finding a completely new scaffold
 
A-77636 is a synthetic drug which acts as a selective D1 receptor full agonist. It has nootropic, anorectic, rewarding and antiparkinsonian effects in animal studies, but its high potency and long duration of action causes D1 receptor downregulation and tachyphylaxis, and unlike other D1 full agonists such as SKF-82,958, it does not produce place preference in animals. A-77636 partially substituted for cocaine in animal studies and has been suggested for use as a possible substitute drug in treating addiction, but it is better known for its use in studying the role of D1 receptors in the brain. So, A-77636 is a Dopamine Agonist that kind of peaked my interest.
 
MedicinalUser247 said:
A-77636 is a synthetic drug which acts as a selective D1 receptor full agonist. It has nootropic, anorectic, rewarding and antiparkinsonian effects in animal studies, but its high potency and long duration of action causes D1 receptor downregulation and tachyphylaxis, and unlike other D1 full agonists such as SKF-82,958, it does not produce place preference in animals. A-77636 partially substituted for cocaine in animal studies and has been suggested for use as a possible substitute drug in treating addiction, but it is better known for its use in studying the role of D1 receptors in the brain. So, A-77636 is a Dopamine Agonist that kind of peaked my interest.
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It doesnt fit the original role of a Selective DRA though, and the D1 downregulation seems rather cumbersome if one hopes to use this recreationally.
 
MedicinalUser247 said:
I'm just waiting to see the day when some Scientist comes up with a Selective DRA full agonist that will just blow peoples Minds.
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A purely selective DRA is unlikely to beat traditional stimulants when it comes to euphoria. Norepinephrine plays a large role in in the reinforcing effects of stimulants. Norepinephrine increases the arousal and reinforcing effects of dopamine. There is a reason why all pure DRIs basically suck in regards to recreational purposes, modafinil and its derivatives and amfonelic acid for example.

Pemoline also technically fits the role of a selective DRA, although its only a mild releaser and mostly creates its effects through reuptake inhibition and some dopamine agonism. It also sucks for recreational purposes.

So yes norepinephrine is required for euphoria, reward, arousal and reinforcing effects when it comes to stimulants. Norepinephrine also indirectly increases dopaminergic neuron firing in the VTA through adrenergic receptors. Adrenoreceptor antagonists have been shown to increase dopamine indirectly following the release of NE while alpha-adrenergic blockers decreased the reinforcing effects of stimulants in rats.
 
MedicinalUser247 said:
I was just wondering about something. Does anyone know if SDRA's exist ? Or what comes closest to a SDRA with no effect on Norepinephrine ? I'd love to read about it if anyone has any information on it. Thanks.

p.s. I only want information Dopamine only. Thanks.
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dextro-N-ethyl-amphetamine.hcl

in my experience
 
Smyth2 said:
idk if you can get a truly selective dopamine releaser design because there is promiscuity between biogenic amine transporters (BATs) and their "native" substrates.

Daws, LC (2009). "Unfaithful neurotransmitter transporters: Focus on serotonin uptake and implications for antidepressant efficacy". Pharmacology & Therapeutics. 121 (1): 89–99. doi:10.1016/j.pharmthera.2008.10.004. PMC 2739988. PMID 19022290.

You can get truly selective DRIs though such as RTI-113.
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Can you find a Cocaine Analogue that doesn't contain a Tropane in the middle of it ? One that also Focuses more on the release on Dopamine rather than Norepinephedine. I want to research this more. Thanks.
 
:cautious: The only reason I don't want it to have a Tropane in it is because it's too hard to draw on my computer. I use Piperidines in place of where ever a Tropane goes.
 
MedicinalUser247 said:
I Designed this https://ibb.co/ycQ7DqJM as a Cocaine Analogue, but I dought it would cause the effective High that I'm looking for. :bigsad:
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At first look I got reminded of the 2-benzyl-piperidine skeleton but that extra nitrogen on there makes it look like a pyrimidine ring, maybe someone more knowledgeable on proper nomenclature could chime in.

However looking at the molecule I doubt it would show much promise as a cocaine replacement. What program are you using to draw btw? You mention difficulty drawing tropanes, does the program you use allow you to input SMILES? You could paste a structure and go from there
 
Releaser/reuptake inhibitor has a large crossover because in fact, they act on the VMAT-2 transport. The reserpine, tetrabenzapine (TZP) and Keranserin sites being key.

(D) Amphetamine is a bit odd becuase it acts as a false substrate as well as acting at the TZP site.

Ligands that bind TO dopamine sites directly are shall we say, 'contraindicated'.

Antidepressants simply display vastly different pharmokinetics to 'stimulants' or 'entactogens'. But both classes demonstrate a bell-shaped dose-response curve.
 
Amfonelic Acid analogs have got my attention now. In studies Amfonelic Acid proved to be potent highly selective Dopamine reuptake inhibitor, but at first it wasn't designed to be a stimulant, but instead an Antibiotic. Which means there could be Analogs made from it that are even more potent and Designed to be more like a Typical Stimulant. One which has a very high DRI/DRA effect to it with a stronger effect on Dopamine, but also doesn't effect Norepinephrine as well. That being said. What would an analog of Amphonelic Acid look like if it was designed to be a Stimulant ?
 
MedicinalUser247 said:
Amfonelic Acid analogs have got my attention now. In studies Amfonelic Acid proved to be potent highly selective Dopamine reuptake inhibitor, but at first it wasn't designed to be a stimulant, but instead an Antibiotic. Which means there could be Analogs made from it that are even more potent and Designed to be more like a Typical Stimulant. One which has a very high DRI/DRA effect to it with a stronger effect on Dopamine, but also doesn't effect Norepinephrine as well. That being said. What would an analog of Amphonelic Acid look like if it was designed to be a Stimulant ?
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The thing is pure DRIs suck for recreational purposes, try it yourself, the -afinils, amfonelic acid, pemoline. No real fun to be had. Norepinephrine plays a key role in arousal and euphoria from stimulants
 
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