23 replies to this topic

[Lemon.]

Hello,

May we please get a 'A-412997' thread going, Thanks.

I will continue:
Please help by discussing studies, purchase sites , experiences , etc.

A-412,997 is a drug which acts as a dopamine agonist that is used in scientific research. It is the first drug developed that is a highly selective agonist for the D4 subtype, with significantly improved selectivity over older D4-preferring compounds such as PD-168,077 and CP-226,269. In animal tests it improved cognitive performance in rats to a similar extent as methylphenidate, but without producing place preference or other signs of abuse liability.Also unlike other dopamine agonists, selective D4 agonists do not cause side effects such as sedation and nausea, and so might have advantages over older dopamine agonist drugs.[4]

Thanks !

How can the edit the topic title, please?.

I would like to remove: Dopamine rDOPAMINE RECEPTOR SENSITIVITY

[tritium]

Group buy?

[Reformed-Redan]

Afraid of DA agonists; but in.

[PAM2]

If there is a realistic chance of group buy, if needed I can help in organizing it, as I have let produced some substances lately (I have sample ISRIB ready, and A-582941 is currently starting), and have two reliable synthesis labs in EU. Of course I would be participating as well.

[Nobility]

bumP

[agora]

I'll need to see how much it costs but if its reasonable I'm in

[knockout_mice]

It is a VERY interesting chemical, but why would anyone want to try it now, when we don't know anything about its toxicity?

 

It hasn't been tested on humans yet. Maybe it's awesome and you get super-focus, or creativity, or sociability for 2-3 hours, but then you can say goodbye to your liver or your D4 receptor containing cells. Who knows? 

 

First, do no harm.

Edited by knockout_mice, 04 May 2014 - 08:21 AM.

[the_apollo]

Afraid of DA agonists; but in.

 

Understandably since existing dopamine agonists tend to downregulate the D1, D2 and D3 receptor expression with chronic use.

 

but what i've read about the D4 receptor, it does not downregulate in response to agonists nor to antagonists, it is also not regulated in the same fashion as the other dopamine receptors.

So a D4 receptor agonist would not result in downregulation of the receptor.

 

I seem to have misplaced the source where i read it, but i'll try to find it.

[sparkk51]

Which receptors are important for planned thinking and working memory?

[xks201]

This has potential. 

[agora]

 

Afraid of DA agonists; but in.

 

Understandably since existing dopamine agonists tend to downregulate the D1, D2 and D3 receptor expression with chronic use.

 

but what i've read about the D4 receptor, it does not downregulate in response to agonists nor to antagonists, it is also not regulated in the same fashion as the other dopamine receptors.

So a D4 receptor agonist would not result in downregulation of the receptor.

 

I seem to have misplaced the source where i read it, but i'll try to find it.

 

 You're totally right

 

http://www.ncbi.nlm....pubmed/19932171

[Reformed-Redan]

Trying to get this to not be reliant on Adderall or methylphenidate. xks201, any chances on getting this?

[AOLministrator]

Has anyone actually have had any experience with this? Some guy is already promoting this stuff as an ADHD cure for some genetically detectable subtype of ADHD?! ... I suppose that this is just longecity style: read the abstract of 2 pilot studies on rodents on pubmed with some untested substance - believe in whatever it possibly indicates as the absolute universal truth. All the time on this forum .. though hope dies last.

[Mind_Paralysis]

I admit... that was foolish of me. I do tend to get quite a bit too enthusiastic about these new compounds.

This compound is still immensely interesting tho', so the fact that there's no more research is puzzling.

I mean, nowhere in the studies do they mention any type of toxicity, or noticeable side-effects at all. It seems perfectly safe.

Yet... no more research?? A COMPLETE abandoning of experimentation?? WHY?!

 

If anyone has some ideas as to why that is, then that would be lovely.

How is research on these new chemicals done tho'? Can we somehow interest leading researchers in picking up research on the drug? Surely there must be a way to do that, to inspire scientists and try to draw to their attention areas worthy of research.

[Metagene]

Odd. I wonder if this is legit?

http://aobious.com/a...rochloride.html

Hmmmm this maybe of some interest.

Dopamine D4 Receptor Excitation of Lateral Habenula Neurons via Multiple Cellular Mechanisms

http://m.jneurosci.o...3/43/16853.full

Edited by Metagene, 14 November 2014 - 06:40 PM.

[Mind_Paralysis]

Interesting stuff metagene... seems like a connection between the glutamatergic and dopamine -systems in the brain. And more specificaly, motivation and reward! = ) Certainly sounds encouraging regarding the compounds potential use, that it mimics the behaviour of a naturally occurring substance that usually regulates this relationship - I_{DAi .}

 

Good find! I'm a bit tired at the moment so I don't know what to make of that Aobious site. Is the price lower than Tocris? The Tocris-site's price was ludicrously high.

 

BTW... this part, was immensely interesting:

 

However, we found that intracellular CaMKII inhibitors did not block the inward currents produced by DA. Similarly, although numerous studies have shown that cAMP produces a depolarizing shift in the voltage sensitivity of HCN channels (Ingram and Williams, 1994; DiFrancesco, 1999; Lüthi and McCormick, 1999), we found that stimulation of cAMP accumulation with forskolin did not block I_DAi in mLHb neurons. Therefore, it does not appear that D₄Rs are coupled to HCN channels via adenylyl cyclase- or CaMKII-dependent mechanisms in these mLHb neurons, and future experiments will focus on identifying the nature of this interaction.

 

 

Help me out with interpreting this note, guys. As some of us know, one of the assumed modes of action of the ADHD-medication Intuniv is that it lowers cAMP in the PFC by affecting the alpha-2 -receptors. This is one of the suspected purposes of the DRD4 -receptors in the PFC, and one of the assumed pathologies of ADHD is errors in the D4 -receptor - therefore not lowering cAMP and allowing the right signals in the right moment.

 

So... the way I read that, is that maybe there ISN'T much of a connection between cAMP and the D4 -receptor?? Hence, the reason why Intuniv actually works... isn't so obvious any more.

On the other hand, they say in the quote that previously, such a connection had been established.

What do you think, fellas? Have I got it all wrong?

Edited by Stinkorninjor, 14 November 2014 - 08:22 PM.

[Metagene]

Tocris wants $519 for 50mg verses $492 for 100mg at Aobious.

[Sunifiramses II]

I would participate in a group buy of this stuff, if only there was one...

[Mind_Paralysis]

Anybody interested in giving feedback on my note on the connection between cAMP, glutamate and the D4 -receptor? Does the study Metagene referenced imply that there isn't as much of a connection as previously thought, or does it not?

 

And I'd be in on a group-buy.

 

Can we find some more intel on the people that invented the compound tho'? I'd be interested in throwing them an e-mail and asking some questions regarding toxicity and such.

 

Meanwhile, since I'm currently studying, I can get through the pay-walls and read up on the documentation. Here's a quick image that details the synthesis of A-412997:
 

 

 

BTW... the EXTREME penile erection side-effect is mentioned in the documentation, quite a bit. So this gets me thinking, for those of us that DON'T, I repeat, DO NOT have any erectile dysfunction, how does one BLOCK this side-effect? Going around dynamic, focused and motivated without hardly any mental or digestive side-effects seems fanstastic, but NOT at the price of a nearly PAINFUL boner - constantly.

Seriously, I don't want a constant boner - do any of you? That stuff is just counter-productive if you're not in a steady relationship.

Edited by Stinkorninjor, 16 November 2014 - 06:29 PM.

[Sunifiramses II]

BTW... the EXTREME penile erection side-effect is mentioned in the documentation, quite a bit.

 

Can you elaborate on this? All I could find with Google (and no way behind paywalls) was another D4 agonist that was being tested for erectile dysfunction.

[Mind_Paralysis]

I'm exaggerating a bit, but the penile erection is mentioned in the documentation. I'll quote ya' a relevant note:

 

 

The selective antagonist, A-381393 (30 μmol/kg), reported to block the effects of PD89211 on penile erection (Nakane et al., 2005), was not sufficient to block the hyperactivity elicited by the administration of A-412997 (data not presented). Given the relatively high dose of A-412997 needed to elicit hyperactivity (3 and 10 μmol/kg) compared to the low doses of dopamine D₄ receptor agonists required for eliciting penile erections (in the same range as those efficacious in cognition models), it is not clear whether 30 μmol/kg of A-381393 would be sufficient to overcome the effects of A-412997.

 

Apparently, it seems like the penile erection side-effect kicks in even at therapeutic low doses, so you'll start to get more of a boner even from the get-go, when you're trying to find your dose. There's a significant overlap between cognitive and penile effects, it would seem.

 

It also says A-412997 doesn't "jack you up" until you take a looot of it tho', which is good.

 

 

http://www.sciencedi...091305705002741

Edited by Stinkorninjor, 17 November 2014 - 04:37 PM.

[datrat]

 

 

And I'd be in on a group-buy.

 

Can we find some more intel on the people that invented the compound tho'? I'd be interested in throwing them an e-mail and asking some questions regarding toxicity and such.

 

 

 

 

I'm in for a group buy. I've got PSSD and something like this would be an interesting experiment for me.

[Metagene]

Anybody interested in giving feedback on my note on the connection between cAMP, glutamate and the D4 -receptor? Does the study Metagene referenced imply that there isn't as much of a connection as previously thought, or does it not?

And I'd be in on a group-buy.

Can we find some more intel on the people that invented the compound tho'? I'd be interested in throwing them an e-mail and asking some questions regarding toxicity and such.

Meanwhile, since I'm currently studying, I can get through the pay-walls and read up on the documentation. Here's a quick image that details the synthesis of A-412997:




BTW... the EXTREME penile erection side-effect is mentioned in the documentation, quite a bit. So this gets me thinking, for those of us that DON'T, I repeat, DO NOT have any erectile dysfunction, how does one BLOCK this side-effect? Going around dynamic, focused and motivated without hardly any mental or digestive side-effects seems fanstastic, but NOT at the price of a nearly PAINFUL boner - constantly.

Seriously, I don't want a constant boner - do any of you? That stuff is just counter-productive if you're not in a steady relationship.

A NOS inhibitor?

Dopamine agonist-induced penile erection and yawning: differential role of D₂-like receptor subtypes and correlation with nitric oxide production in the paraventricular nucleus of the hypothalamus of male rats.

http://www.ncbi.nlm....ubmed/22391116/


Ro10-5824 doesn't have this issue from what I understand.

Edited by Metagene, 19 November 2014 - 02:07 AM.

[Mind_Paralysis]

 

Anybody interested in giving feedback on my note on the connection between cAMP, glutamate and the D4 -receptor? Does the study Metagene referenced imply that there isn't as much of a connection as previously thought, or does it not?

And I'd be in on a group-buy.

Can we find some more intel on the people that invented the compound tho'? I'd be interested in throwing them an e-mail and asking some questions regarding toxicity and such.

Meanwhile, since I'm currently studying, I can get through the pay-walls and read up on the documentation. Here's a quick image that details the synthesis of A-412997:




BTW... the EXTREME penile erection side-effect is mentioned in the documentation, quite a bit. So this gets me thinking, for those of us that DON'T, I repeat, DO NOT have any erectile dysfunction, how does one BLOCK this side-effect? Going around dynamic, focused and motivated without hardly any mental or digestive side-effects seems fanstastic, but NOT at the price of a nearly PAINFUL boner - constantly.

Seriously, I don't want a constant boner - do any of you? That stuff is just counter-productive if you're not in a steady relationship.

A NOS inhibitor?

Dopamine agonist-induced penile erection and yawning: differential role of D₂-like receptor subtypes and correlation with nitric oxide production in the paraventricular nucleus of the hypothalamus of male rats.

http://www.ncbi.nlm....ubmed/22391116/


Ro10-5824 doesn't have this issue from what I understand.

 

 

Great find, Metagene! = ) A partial agonist, yet HIGHLY selective, might just be what the dr ordered... Ro10-5824, you say? Let's have a look at that sucker...

 

If there's an option to take LESS drugs, then I say that's the better one. The whole point of my own personal interest in A-412997 is that it seemed to be side-effect -free.

 

Of course, the one side-effect it has is significantly LESS bothersome than those of traditional stimulants, or Modafinil for that matter, but still, a side-effect.

 

EDIT: We should probably make a new thread for Ro10-5824 tho'. It's worth a whole new thread there. It seems to be somewhat less D4 -selective than A-412997, but since it's still 250 times more active at D4 than D3 then it does still seem like a highly interesting compound.

Edited by Stinkorninjor, 19 November 2014 - 09:54 PM.