Would a D1/D5 receptor full agonist have recreational properties?

[purplehaze147]

I've been wondering this for a while. There are no drugs out there that are primarily dopamine agonists that are known to be used recreationally by humans. Isn't dopamine the primary pleasure neurotransmitter? Or would that be endorphines? Activation of the MOR results in dopamine release so I don't know if the pleasure is from the endorphine/opioid agoinism or dopamine release, I think it's from both.

Ropinirole (Requip) is a full agoinist of the D2 receptor & a (partial?) agonist of the D3 & D4 receptors. It definitely doesn't have recreational value. If you take too much you will just become nauseous & may have other negative side effects. This shows it has to be D5R and/or D1R that cause euphoria. D5R is the likely candidate that causes euphoria since it's found in the central part of the brain, where the pleasure center is located, D1R is found in the central nervous system.

SKF-81,297 is a selective D1R & D5R full agoinist. It has been shown to cause self administration, hyperactivity, & anorexia in animal studies. I may have just answered my own question but you'd think a selective D1R/D5R agonist would be a popular recreational drug by now if it was any good or at least an available research chemical?

Dihydrexidine, another selective D1R/D5R full agonist, has been shown to cause hypotension. This is interesting because the side effect I dislike the most from dopamine releasing stimulants is hypertension (also the comedown). The hypotension is probably caused by the brain releasing less dopamine as a result of the dopamine receptor agonism. Dopamine gets metabolized into norepinepherine, norepinepherine causes hypertension, anxiety, & insomnia. SKF-81,297 showed stimulant type behavior in animals. Imagine a stimulant with all the euphoria & productivness with none of the negative side effects. Wouldn't that be great?

So why hasn't a selective D1R/D5R agonist emerged as a recreational drug yet?

 

[Zeds(NCO2CH2CH3)2]

I was going to go on a tangent as to why just standalone increased synaptic Dopamine is worthless but I decided not to.

The simple answer is this class of drugs has a unique pharmacophore that involves a dihydroxy benzazepine moiety, free catechol are notoriously unstable due to formation of phase one quinone moieties(REDOX REACTIVE) as well as conjugated phase two compounds . As well as benzazepine being increasingly more basic than the tetrahydroquinoline counterparts, and thus they are more readily ionized, in summary poor oral availability, I'm guessing the Apes received these drugs parentally.

I'm going to hold back to see others replies but Dopamine isn't the only player in the football game...
Zedsdead

 

[Jonneh]

I was going to go on a tangent as to why just standalone increased synaptic Dopamine is worthless but I decided not to.

Aww, that sounds fun though!

 

[Solipsis]

What would be pretty much required moieties in potent dopamine receptor agonists according to classical models?

 

[Zeds(NCO2CH2CH3)2]

Well I don't have time to elaborate now but look at the amphetamine, aminorex, pemoline, and cocaine example, if you try really hard you can see that they are all very similar literally overlay pharmacophore(draw triangles and judge angstrom distance) , it's just amphetamine clearly binds to 'less' residues because all it can do it pi pi stack, van Der walls interact(alkyl chain) and hydrogen bond, and hydrogen bond accept(twice-three time), still a decent amount of interaction.

Still The base pharmacophore is recognition of the aromatic moiety and then association of the ionized ammonium ion. Some might say the higher Sigma electron density at the amine and high pi density at the ring appx 3-4 angstrom room away is essential. But this could just be the way it interacts with the transmembrane domains.

Can easily be determined by comparing the transmembrane domains involved with cocaine, aminorex, amphetamine, and pemoline and compare them but I'm not sure if they are totally known.

There are actually alot of good parental Dopamine agents but they are short acting, highly abusable, and not safe long term. Try to administer them Orally and you get coconuts, nothing, some drugs are just optimized as in vitro drugs or parental drugs,. Some just can't be optimized so they do assays with what they can, excite who they can, get whatever Grant money they can, then move on (see common practice).

Note that these drugs are generally either way too short or way to long and toxic, the medium and gold standard has and will continue to be amphetamine..

 

[purplehaze147]

I was going to go on a tangent as to why just standalone increased synaptic Dopamine is worthless but I decided not to.

I'm going to hold back to see others replies but Dopamine isn't the only player in the football game...
Zedsdead

Why would it be worthless? I don't think amphetamines euphoria is related to an increase in norepinepherine. But maybe it's the dopamine increase along with the TAAR agoinism (which just in turn releases more dopamine & norepinepherine) & MAOI activity? And here I'm talking about direct dopamine agonism which would most likely reduce sysnaptic levels of dopamine.

 

[atara]

Dihydrexidene *was* this. If it was reinforcing, wouldn't we know? Also, the hypotension was severe enough for the research to be discontinued, which tells me it's probably not a minor side-effect.

After all, despite decades of dogma, both opioids and nicotinoids are evidently more reinforcing than dopaminergic stimulants.

 

[Zeds(NCO2CH2CH3)2]

Euphoria is not correlated to concentration of synaptic Dopamine our purplehaze, nor adrenaline. Euphoria could be said to correlated to the rate of Flux of these neurotransmitters and the subsequent "propelled binding". It not matters the concentration due so but the exchange rate, see the concept of "Gibbs free energy" . And depolarization etc, note that it's far from black and white.

Let's say drug A toggles a Dopamine Receptor at a high enough rate of binding to elicit an intracellular response, now the intracellular response is dependent on rate of the drug of the binding to the receptor. Now consider drug B, say the binding is slow, then in this case physiological function may be halted or actually constitutionally stimulated(Inverse agonist).

Now consider the rate of the intracellular response or release etc to the synaptic membrane, which is dependent on various factors most notably the Flux example first proposed. If drug b binds so poorly then in the synapse the Flux of Dopamine will be incredibly slow and the "propelled molecules" (Lol at this example) will not have a high enough concentration at a given mount of time, with a given amount of energy.

Therefore without this the Dopamine swimming around is essentially worthless, it still gets degraded, it still gets recycled, note that when people consider Dopamine, your daily concentration is around the same but at any point it's NOT the same molecules they are being recycled at a constant rate. Essentially you are thermodynamically competing with Dopamine normal binding, and it's recycling, in simplest terms.

Binding is dependent on so many things, and in the end Dopamine may bind at a higher rate due to initial Flux, to toggle a GABAB Receptor for example, which are directly connected to many complex processes including nociception(opiate receptors) and nmda receptors etc..
Hope this helps
Zedsdead

 

[purplehaze147]

^Yea that helps thanks

 

[endotropic]

Well let's not write this one off too quickly. You can find reports all over the internet of L-DOPA producing euphoriant type effects at high doses. What primary mechanism of action can explain those effects if not direct dopamine receptor agonism?

 

[:DNA]

Euphoria is not correlated to concentration of synaptic Dopamine our purplehaze, nor adrenaline. Euphoria could be said to correlated to the rate of Flux of these neurotransmitters and the subsequent "propelled binding". It not matters the concentration due so but the exchange rate, see the concept of "Gibbs free energy" . And depolarization etc, note that it's far from black and white.

Let's say drug A toggles a Dopamine Receptor at a high enough rate of binding to elicit an intracellular response, now the intracellular response is dependent on rate of the drug of the binding to the receptor. Now consider drug B, say the binding is slow, then in this case physiological function may be halted or actually constitutionally stimulated(Inverse agonist).

Now consider the rate of the intracellular response or release etc to the synaptic membrane, which is dependent on various factors most notably the Flux example first proposed. If drug b binds so poorly then in the synapse the Flux of Dopamine will be incredibly slow and the "propelled molecules" (Lol at this example) will not have a high enough concentration at a given mount of time, with a given amount of energy.

Therefore without this the Dopamine swimming around is essentially worthless, it still gets degraded, it still gets recycled, note that when people consider Dopamine, your daily concentration is around the same but at any point it's NOT the same molecules they are being recycled at a constant rate. Essentially you are thermodynamically competing with Dopamine normal binding, and it's recycling, in simplest terms.

Binding is dependent on so many things, and in the end Dopamine may bind at a higher rate due to initial Flux, to toggle a GABAB Receptor for example, which are directly connected to many complex processes including nociception(opiate receptors) and nmda receptors etc..
Hope this helps
Zedsdead

fascinating stuff, thanks for sharing

 

[endotropic]

Euphoria is not correlated to concentration of synaptic Dopamine our purplehaze, nor adrenaline. Euphoria could be said to correlated to the rate of Flux of these neurotransmitters and the subsequent "propelled binding". It not matters the concentration due so but the exchange rate, see the concept of "Gibbs free energy" . And depolarization etc, note that it's far from black and white.

Let's say drug A toggles a Dopamine Receptor at a high enough rate of binding to elicit an intracellular response, now the intracellular response is dependent on rate of the drug of the binding to the receptor. Now consider drug B, say the binding is slow, then in this case physiological function may be halted or actually constitutionally stimulated(Inverse agonist).

Now consider the rate of the intracellular response or release etc to the synaptic membrane, which is dependent on various factors most notably the Flux example first proposed. If drug b binds so poorly then in the synapse the Flux of Dopamine will be incredibly slow and the "propelled molecules" (Lol at this example) will not have a high enough concentration at a given mount of time, with a given amount of energy.

Therefore without this the Dopamine swimming around is essentially worthless, it still gets degraded, it still gets recycled, note that when people consider Dopamine, your daily concentration is around the same but at any point it's NOT the same molecules they are being recycled at a constant rate. Essentially you are thermodynamically competing with Dopamine normal binding, and it's recycling, in simplest terms.

Binding is dependent on so many things, and in the end Dopamine may bind at a higher rate due to initial Flux, to toggle a GABAB Receptor for example, which are directly connected to many complex processes including nociception(opiate receptors) and nmda receptors etc..
Hope this helps
Zedsdead

I'm...really not sure what you're saying. Rates of binding and dissociation determine the affinity of a drug or neurotransmitter for a receptor, not the agonist vs antagonist properties. An inverse agonist can bind to a receptor so tightly and for so long that the cell will degrade the receptor before the drug dissociates, and an agonist can do the exact same thing, so rates of flux really have nothing to do with it.

 

[Zeds(NCO2CH2CH3)2]

?????? Perhaps your thermodynamics is rusty my friend! Read between the lines and it will make sense. Rates of Flux are absolutely critical! Look at how any drug binds to the Receptor, where does the actual chemical response come from???? Inside the neuron of course, think about the processes that are triggered as a result of binding inside of the cell, even consider the true thermodynamic identity of the binding equation we all know and love and you will see its direct definition is with regards to entropy and the concept of free energy.

These are free energy relationships, I was explaining the MAJOR biochem101 rule of binding-->conformation change-->removal of a molecule or ion to reattain thermodynamic balance. (basic model we know this is an infinite cycle)
Consider an action potential and a sodium ion, and the membrane read about the equations for this and now apply it to our example.

The bottom line is increased concentration of neurotransmitters doesn't do much and concentrations may not be increased at all in drugs of abuse, rather whatever transient change occurs is swiftly normalized and the resultant system takes a hit leading to upregulation of other proteins which are activated in need to normalize everything (protein kinase A, and friends)..

Just realize there is pharmacology 101 and then there is the screwed up reality of pharmacology in where the difficulty in explaining Is real, I may have skipped some initial break downs but to those that are familiar with thermodynamics and concepts therein I hope you appreciate some more knowledge... Google neurotransmitter Flux membrane for more information..
Zedsdead

 

[serotonin2A]

Well I don't have time to elaborate now but look at the amphetamine, aminorex, pemoline, and cocaine example, if you try really hard you can see that they are all very similar literally overlay pharmacophore(draw triangles and judge angstrom distance) , it's just amphetamine clearly binds to 'less' residues because all it can do it pi pi stack, van Der walls interact(alkyl chain) and hydrogen bond, and hydrogen bond accept(twice-three time), still a decent amount of interaction.

Still The base pharmacophore is recognition of the aromatic moiety and then association of the ionized ammonium ion. Some might say the higher Sigma electron density at the amine and high pi density at the ring appx 3-4 angstrom room away is essential. But this could just be the way it interacts with the transmembrane domains.

Can easily be determined by comparing the transmembrane domains involved with cocaine, aminorex, amphetamine, and pemoline and compare them but I'm not sure if they are totally known.

There are actually alot of good parental Dopamine agents but they are short acting, highly abusable, and not safe long term. Try to administer them Orally and you get coconuts, nothing, some drugs are just optimized as in vitro drugs or parental drugs,. Some just can't be optimized so they do assays with what they can, excite who they can, get whatever Grant money they can, then move on (see common practice).

Note that these drugs are generally either way too short or way to long and toxic, the medium and gold standard has and will continue to be amphetamine..

How would you go about directly overlaying amphetamine and cocaine? It's not possible. I will admit that there are similarities between methylphenidate and some of the RTI/WIN compounds (cocaine analogs with the ester group removed), but you are still never going to get them to directly overlay with because the cocaine analogs have an extra carbon linker. In all likelyhood there are substantial differences in the pharmacology of cocaine/methylphenidate and some of the other drugs you listed that act as releasers.

 

[serotonin2A]

Euphoria is not correlated to concentration of synaptic Dopamine our purplehaze, nor adrenaline. Euphoria could be said to correlated to the rate of Flux of these neurotransmitters and the subsequent "propelled binding". It not matters the concentration due so but the exchange rate, see the concept of "Gibbs free energy" . And depolarization etc, note that it's far from black and white.

Let's say drug A toggles a Dopamine Receptor at a high enough rate of binding to elicit an intracellular response, now the intracellular response is dependent on rate of the drug of the binding to the receptor. Now consider drug B, say the binding is slow, then in this case physiological function may be halted or actually constitutionally stimulated(Inverse agonist).

Now consider the rate of the intracellular response or release etc to the synaptic membrane, which is dependent on various factors most notably the Flux example first proposed. If drug b binds so poorly then in the synapse the Flux of Dopamine will be incredibly slow and the "propelled molecules" (Lol at this example) will not have a high enough concentration at a given mount of time, with a given amount of energy.

Therefore without this the Dopamine swimming around is essentially worthless, it still gets degraded, it still gets recycled, note that when people consider Dopamine, your daily concentration is around the same but at any point it's NOT the same molecules they are being recycled at a constant rate. Essentially you are thermodynamically competing with Dopamine normal binding, and it's recycling, in simplest terms.

Binding is dependent on so many things, and in the end Dopamine may bind at a higher rate due to initial Flux, to toggle a GABAB Receptor for example, which are directly connected to many complex processes including nociception(opiate receptors) and nmda receptors etc..
Hope this helps
Zedsdead

I'm sorry, I'm really having a really hard time following you because you are using phrases that are not standard for pharmacology/biochemistry.

"thermodynamically competing" is usually called competitive binding

by "propelled molecules", I think you mean agents with high efficacy

by "toggles" do you mean activate?

neurotransmitter flux usually refers to release, but here you seem to be talking about binding because you say that the binding of other drugs can influence dopamine flux. I'm not sure how that would happen, unless you are talking about the other drugs binding to presynaptic dopamine autoreceptors.

The response to a drug isn't determined by the binding rate, it is determined by the efficacy (although it helps if the drug remains bound to the receptor for a long time because then it can continue to induce a response). A partial agonist with a high on/off rate will still be a partial agonist. The efficacy is determined by the specific range of receptor isoforms the drug can stabilize. If the particular receptor isoforms that are stabilized have low affinity for the effector proteins then there will be relatively little downstream response.

How can you say that the response to dopamine isn't due to the concentration? That is ultimately what determines the level of receptor activation/intracellular response.

Euphoria is not correlated with either dopamine concentration, or what you refer to as "dopamine flux", because dopamine does not directly cause euphoria. It's action is much more complex then that. There are tonic and phasic types of dopamine release that produce different effects and have vastly different functions, and the effects vary by brain region.

 

[Zeds(NCO2CH2CH3)2]

Please read all pure lock and key model enthusiasts, brush up on your thermodynamics..

Biogenic amine transporters: just when you thought you knew them

(It is a free pdf)
For a review on what I am explaining until then I am done derailing this thread.
Peace
Zedsdead

 

[serotonin2A]

Please read all pure lock and key model enthusiasts, brush up on your thermodynamics..

Biogenic amine transporters: just when you thought you knew them

(It is a free pdf)
For a review on what I am explaining until then I am done derailing this thread.
Peace
Zedsdead

This thread is about dopamine receptors, not the transporter, so i'm not sure how reading about the thermodynamics of transport would be relevant. The fact is that whether you believe in a lock and key model of receptor action or the induced-fit model, neither model explains partial agonist activity on the basis of how long the receptor is occupied or the number of association-dissassociation cycles. It is explained by subtle differences in the tertiary conformation of the receptor, which prevent the ligand-receptor complex from producing the maximum level of effector activation that is possible. However, with GPCRs the induced-fit model fails to explain receptor constitutive activity, since there is no ligand to "induce" the active state. And all of the recent literature comparing the two models seems to favor a modified version of the lock and key model that can accomidate agonist trafficking.

Reading about transporter thermodynamics also wouldn't clarify the language you were using, which is why I was hoping you could explain what you were saying. In my mind "toggling" a receptor could mean many things, for example driving the receptor-G protein complex through one or more cycles of signaling, flipping the receptor from a nonphosphorylated to a phosphorylated state, changing whether the receptor is coupled to G proteins, or internalizing the receptor by endocytosis. All of those things would potentially be influenced by binding. I'm not trying to be an ass, I just want to understand your post.

 

[St3ve]

Well let's not write this one off too quickly. You can find reports all over the internet of L-DOPA producing euphoriant type effects at high doses. What primary mechanism of action can explain those effects if not direct dopamine receptor agonism?

There's also studies showing dopamine release in response to negative stimuli in animal models. There's also plenty of evidence that extra dopamine =/= extra pleasure. Dopamine is undoubtedly involved in the reward pathway, but doesn't seem to cause the sense of achievement or pleasure.

From my thesis:

Matsumoto and Hikosaka recorded from dopaminergic neurons in the SN and the VTA. Monkeys were trained in a Pavlovian conditioning task with two distinct contexts, one that had positive outcome (liquid reward) and one with a negative outcome (air puff to the eye). They found that some dopamine neurons were excited by reward predicting cues and inhibited by cues that predicted punishment. However, some neurons fired in response to both cues and some fired in response to the aversive cue and were inhibited by the reward predicting cue. Neurons that fired in response to the reward predicting cue tended to be located ventromedially in the SN and VTA whereas neurons that fired in response to the aversive cue were located dorsolaterally in the SN (Matsumoto and Hikosaka, 2009).

|
SN= substantia nigra
VTA= ventral tegmental area

Dopamine signalling in the midbrain has long been associated with reward (Volkow et al., 1999). Initally it was thought that dopamine acted as a “pleasure” neurotransmitter, which mediated the hedonic impact of reward (Wise, 1980). This idea was based on research that showed that dopamine levels were increased in response to pleasurable activities such as food and sex (Hernandez and Hoebel, 1988; Damsma et al., 1992). This has now largely disproven as pleasure responses measured in rats in response to sweet rewards were unaffected by lesions of dopaminergic neurons (Berridge et al., 1989). Similarly, genetically altered hyperdopaminergic mice do not display an increased hedonic response to sweet rewards (Peciña et al., 2003), and dopamine receptor agonists do not increase palatability (Kaczmarek and Kiefer, 2000).
Instead of mediating the ‘liking’ component of reward, the hedonistic component, it appears as though dopamine mediates the ‘wanting’ component of reward (Berridge, 2007). ‘Wanting’ in this case refers to the concept of incentive salience which posits that dopamine mediates a dynamic attribution of salience to otherwise neutral stimuli, making them more appealing and motivationally ‘wanted’ by the organism. Support for this theory comes from research in the field of addiction. Most drugs of abuse affect dopamine signaling and drug addicts often report a loss of pleasure in their drug of choice, yet still feel compelled to keep taking it (Goldstein et al., 2010). Animal studies have shown that hyperdopaminergic mice are more motivated to obtain a sweet reward, yet do not appear to ‘like’ it anymore than controls (Peciña et al., 2003).

 

[serotonin2A]

That's an excellent point, dopamine doesn't produce euphoria, but it is involved in motivation. Dopamine release increases when people are craving cocaine, which is definitely not a pleasant state. If rodents are given cocaine repeately in a specific environment, then dopamine relase increases if the animals are re-exposed to the environment. That appears to be why abstinent drug addicts experience craving if they return to places associated with past drug use. At least under those conditions dopamine is not producing pleasure but is acting as a reward predictor. It is driving drug "wanting", which motivates or drives the action required to acquire and ingest a drug.

 

[endotropic]

I'm not denying Berridge et al.'s theories about dopamine relating to incentive salience and motivation and what not, but I also can't deny the evidence that pharmacological increases in global dopamine signaling produce euphoric responses in humans.

How else can you explain euphoric reactions to high dose d-amph?