Juicewrldfan
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Looking at mechanisms of actions it says amphetamine is a binder at d2, thats their way of saying agonist I take it?
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N&PD Moderators: Skorpio | thegreenhand
Drug Bank - Binder?
- Thread starter Juicewrldfan
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I don't think so, as it describes amphetamine as an agonist/antagonist at other sites (VMAT2 for example as it's primary mechanism of action).
Frankly i find it quite weird, and i didn't see a reference for that d2 binder fact, and a quick Google didn't yield any papers that substantiate that fact (d2 receptors are involved in amphetamine's effects, but they are activated by dopamine). I have always read/been taught that amphetamine is a monoamine releaser, and doesnt have direct agonism at any of the major monoamine receptors. I believe this to be true as pretreatment with drugs which deplete vesicles of monoamines, such as reserpine are sufficient to block the effects of amphetamine, which indicates that dopamine release is necessary for the locomotor stimulation (if amphetamine was a direct agonist, it should still exert effects in the absence of dopamine release).
Frankly i find it quite weird, and i didn't see a reference for that d2 binder fact, and a quick Google didn't yield any papers that substantiate that fact (d2 receptors are involved in amphetamine's effects, but they are activated by dopamine). I have always read/been taught that amphetamine is a monoamine releaser, and doesnt have direct agonism at any of the major monoamine receptors. I believe this to be true as pretreatment with drugs which deplete vesicles of monoamines, such as reserpine are sufficient to block the effects of amphetamine, which indicates that dopamine release is necessary for the locomotor stimulation (if amphetamine was a direct agonist, it should still exert effects in the absence of dopamine release).
Juicewrldfan
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As always @Skorpio we know we can always count on you and a few others like @AlsoTapered….to break things down like this for us.
AlsoTapered
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D2 ligands tend be neuroleptics (antagonist) or for the symptomatic treatment of Parkinson's disease (agonists) and both produce very unpleasant side-effects.
As Skorpio mentioned, I was taught that amphetamines act on the VMAT2 transports. Amphetamine binding at the tetrabenzapine site and methamphetamine, methylphenidate & phenmetrazine at the reserpine site.
I don't know if that difference is as simple as amphetamine being a primary amine and the other being secondary amines, but it's sort of interesting that the body does treat them slightly differently.
BTW if you ever want to see how badly wrong RCs can go, look up 'The Case of the Frozen Addicts' in which badly made MPPP contained MPTP that proved to destroy the substantia nigra in a matter of HOURS so perfectly healthy people developed Parkinson's overnight.
Sooner or later another RC is going to turn up and result in a similar disaster. Already people are making ring-halogenated cathinones which I strongly suspect are neurotoxic.
As Skorpio mentioned, I was taught that amphetamines act on the VMAT2 transports. Amphetamine binding at the tetrabenzapine site and methamphetamine, methylphenidate & phenmetrazine at the reserpine site.
I don't know if that difference is as simple as amphetamine being a primary amine and the other being secondary amines, but it's sort of interesting that the body does treat them slightly differently.
BTW if you ever want to see how badly wrong RCs can go, look up 'The Case of the Frozen Addicts' in which badly made MPPP contained MPTP that proved to destroy the substantia nigra in a matter of HOURS so perfectly healthy people developed Parkinson's overnight.
Sooner or later another RC is going to turn up and result in a similar disaster. Already people are making ring-halogenated cathinones which I strongly suspect are neurotoxic.
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Why do you think the ring halogenated cathinones are neurotoxic? Just wondering what you think the mechanism might be
AlsoTapered
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Well, I should have been more explicit. The neurotoxicity of the ring-halogenated amphetamines and methamphetamine appears to be para -I > Br >Cl > F and all of those were made, tested and were proven to be neurotoxic. Their are already a few reports on para halogenated cathinones that describe the same damage. But I'm reasonably confident that those initial findings will be substantiated.
Now the meta substituted amphetamine (which, BTW, are sold as entactogens in some nations) are not well researched BUT the one meta halogenated cathinone we have a lot of data on, bupropion is tacitly considered to be neurotoxic. Their are certainly animal studies showing that it's neurotoxic.
As for ortho halogenated amphetamines. Well, nobody made them back in the day although 2-fluoroamphuetuamine and 2-fluoromethamphetamine have both shown up as RCs,
It's also worth remembering that fenfluramine turned out to be cardiotoxic. That was of 5HT2b affinity and I strongly suspect that at least ortho and meta -Cl and -F will lend similar affinity. -CF3 like -Cl and -F make pretty reasonable hydrogen-bond acceptors.
We shouldn't forget that the 2,5-dimethoxy pattern demonstrates both 5H2a and 5HT2b affinity BUT far more to 5HT2a. Mono ortho or meta methoxy produces less overall affinity and isn't as selective.
I think it was fascinating that Dr. Shulgin discovered the key 2,5-dimethoxy pattern and explored it, but I'm more 'on message' with Dr. Nichols who has always been very careful to test for toxicity and not, to my knowledge, ever taken ANY of those compounds.
It was Dr. Nichols who I sent the QSAR of the ring-substituted aminorex series to. I WAS going to continue the study on the 4-methylaminorex series but he pointed out that some of them demonstrated potent MAOI activity... so I didn't.
Now the meta substituted amphetamine (which, BTW, are sold as entactogens in some nations) are not well researched BUT the one meta halogenated cathinone we have a lot of data on, bupropion is tacitly considered to be neurotoxic. Their are certainly animal studies showing that it's neurotoxic.
As for ortho halogenated amphetamines. Well, nobody made them back in the day although 2-fluoroamphuetuamine and 2-fluoromethamphetamine have both shown up as RCs,
It's also worth remembering that fenfluramine turned out to be cardiotoxic. That was of 5HT2b affinity and I strongly suspect that at least ortho and meta -Cl and -F will lend similar affinity. -CF3 like -Cl and -F make pretty reasonable hydrogen-bond acceptors.
We shouldn't forget that the 2,5-dimethoxy pattern demonstrates both 5H2a and 5HT2b affinity BUT far more to 5HT2a. Mono ortho or meta methoxy produces less overall affinity and isn't as selective.
I think it was fascinating that Dr. Shulgin discovered the key 2,5-dimethoxy pattern and explored it, but I'm more 'on message' with Dr. Nichols who has always been very careful to test for toxicity and not, to my knowledge, ever taken ANY of those compounds.
It was Dr. Nichols who I sent the QSAR of the ring-substituted aminorex series to. I WAS going to continue the study on the 4-methylaminorex series but he pointed out that some of them demonstrated potent MAOI activity... so I didn't.
AlsoTapered
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BTW it appears that aminorex, pemoline & pipradrol all bind at the reserpine site. THAT might suggest that the active tautomers ofaminorex and pemoline are in fact the endo-amine. So does cocaine, BTPC and amfonelic acid and they all have tertiary amines.
I mean, I don't think anyone has ever systematically gone through all of the psychostimulants and noted which site they bind to and I'm only GUESSING that it's due to the amine being primary or secondary/tertiary.
If someone could find out where cypenamine binds, that would lend a weight of evidence.
As for those newer stimulants without a basic nitrogen, well modafinil binds at the tetrabenzapine site... others, no idea.
I mean, I don't think anyone has ever systematically gone through all of the psychostimulants and noted which site they bind to and I'm only GUESSING that it's due to the amine being primary or secondary/tertiary.
If someone could find out where cypenamine binds, that would lend a weight of evidence.
As for those newer stimulants without a basic nitrogen, well modafinil binds at the tetrabenzapine site... others, no idea.
Juicewrldfan
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Thanks everyone. So in case anyone is reading this that doesn’t know of drug bank knows what we were looking at…
go.drugbank.com
Dextroamphetamine saccharate | DrugBank Online
go.drugbank.com
Juicewrldfan
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Yeah but I don’t want to live without my cognitive abilities. I don’t want them to deteriorate so it’s a fat NO for me if they are nuerotoxic…some say amphetamines strobes are toxic in therapeutic doses but again not great research that proves that…
lol- and I know you are not trying to convince anyone what to do…I’m just saying my opinion. Sorry been on Reddit too much lately. I can only take Reddit in small doses and I feel like I have to over explain myself because people take things way out of context and attack you on Reddit at any opportunity to misconstrue the words. Most scientific research like using brain scans to prove gender theory often it’s a “you’re a racist or transphobe “ because I do not believe most of the research is good research…external stimuli can change brain structure and they were doing brain scans on dead people who took hormones of the opposite gender for years…and they are like woohoo this proves it!!!
Side note: (please feel free to skip this portion)
it’s wild because I was very clear that I was just disagreeing with the quality of research…
And they banned me…I was very clear and even said that I have great compassion for those suffering from gender dysphoria but I just simply do not believe that encouraging people to go strait to hormones and strait to “we need to affirm that they are the opposite sex” is compassionate. I think it’s misguided instructions that caring therapist are following and validating someone questioning their gender and to me I’ll be very honest, please no one get upset. Thinking they are helping them.
I really mean this in love, but I think most(not all) of the time we are encouraging people to live in this altered reality…it’s like validating someone’s hallucinations to me. It’s not compassionate to convince people to pursue a delusion and live in it and that has severe consequences. Some are likely truly trans. I just don’t think it’s as common as it is becoming…
K side note off:
lol- and I know you are not trying to convince anyone what to do…I’m just saying my opinion. Sorry been on Reddit too much lately. I can only take Reddit in small doses and I feel like I have to over explain myself because people take things way out of context and attack you on Reddit at any opportunity to misconstrue the words. Most scientific research like using brain scans to prove gender theory often it’s a “you’re a racist or transphobe “ because I do not believe most of the research is good research…external stimuli can change brain structure and they were doing brain scans on dead people who took hormones of the opposite gender for years…and they are like woohoo this proves it!!!
Side note: (please feel free to skip this portion)
it’s wild because I was very clear that I was just disagreeing with the quality of research…
And they banned me…I was very clear and even said that I have great compassion for those suffering from gender dysphoria but I just simply do not believe that encouraging people to go strait to hormones and strait to “we need to affirm that they are the opposite sex” is compassionate. I think it’s misguided instructions that caring therapist are following and validating someone questioning their gender and to me I’ll be very honest, please no one get upset. Thinking they are helping them.
I really mean this in love, but I think most(not all) of the time we are encouraging people to live in this altered reality…it’s like validating someone’s hallucinations to me. It’s not compassionate to convince people to pursue a delusion and live in it and that has severe consequences. Some are likely truly trans. I just don’t think it’s as common as it is becoming…
K side note off: