kingdxm
02-09-2007, 11:56 PM
OK, I would like to throw my 2 cents in on the loperamide subject. I would like to say that I have read just about everything that concerns the possibility of making this drug psychoactive. I believe that someday this drug can be made active, but only time will tell. Here are the things I have read:
Polysorbate-80 binding: this calls for binding this compound to loperamide so that it passes the BBB and a substance called P-glycoprotein(which I will mention later), and according to the reports it seems to have been reasonably affective. Unfortunately I doubt that anyone of us has the ability to duplicate this process, unless you have a lot of money and a sophisticated lab at home.
Oxidation of the hydroxyl molecule: I have heard talk of this one, sort of like oxidizing ephedrine to get methcathinone. Forget it. Oxidizing a tertiary alcohol is virtually impossible and even if you could do it, you would end up with a double bond somewhere in the vicinity of where the alcohol molecule was, possibly making a dangerous compound similar to MPTP. MPTP was a byproduct of the manufacture of a Demerol analog called MPPP. the MPTP caused almost instant advanced Parkinson's disease in the user, freezing them up like a statue. So of these people were found with the needles still stuck in their arms!!! Fuck that! And even if you didn't produce a dangerous by product what makes you think the drug would be active? Opiates need a quaternary carbon as part of their activity. The only exception to this rule is the fentanyl compounds(which have a nitrogen where the quaternary carbon would be), thiambutene(not used in the US), and salsolinol(a bicyclic form of dopamine, which activates opiate mu receptors but because of it's shape, it gets locked into the receptor, causing an antagonistic effect shortly after).
BTW, a quaternary carbon is a carbon atom that have 4 separate functional groups attached to it, causing it to have a chiral center. this is very important in opiate chemistry. Look at any opiate compound and you will find it(except gor the ones I stated above)
Reduction and dehalogenation: Again reduction will change the cirality of the Q-carbon, and besides do we really know if the alcohol has anything to do with it's BBB activity? There are so many lipid soluble portions to this drug that the alcoholic functional group should make very little difference in it's solubility in fatty tissue. Ephedrine penetrates the BBB, just not as good as methamphetamine. Besides, meth's higher affinity for dopamine receptors that ephedrine isn't just based on it's higher lipid solubility, but also in part due to it's closer resemblance to dopamine( due to the lack of the hydroxyl group). As far as dehalogenation goes, that is a question mark. The chlorine atom would make loperamide more lipid soluble than if it were replaced with a hydrogen atom. One thing I must say is that the chlorine and the alcohol may be the binding sites for P-glycoprotein on the loperamide molecule.
Acetylation: It is reasonable to say that an acetyl group(or even propionic acid) would make loperamide more fat soluble, but we don't know for sure that higher lipid solubility is what it needs. Either of these compounds may still have a high affinity for binding to P-glycoproteins, which is defiantly a big reason why loperamide doesn't enter the brain. Only serious experimentation in this area will reveal if this is effective.
Loperamide combined with P-glycoprotein-inhibiting drugs: This too has been tried with some success. Drugs such as Cereport, citalopram, fluoxetine, fluvoxamine, paroxetine, reboxetine, sertraline, venlafaxine, quinidine, ketoconazole, retonivir, cyclosporine A, and Erythromycin. Of the naturally occurring chemicals Curcumin, ginsenosides, piperine(from black pepper), some catechins from green tea, and silymarin from milk thistle were found to be inhibitors of Pgp, while some catechins from green tea increased Pgp-mediated drug transport by heterotropic allosteric mechanism, and St. John's wort induced the intestinal expression of Pgp in vitro and in vivo. Some components (e.g., bergamottin and quercetin) from grapefruit juice were reported to modulate Pgp activity.
Personally I have tried quercerin(found in good concentrations in grapefruit) and found it to be ineffective. Of all of these, the only ones I have found on the web to have been effective in testing was Cereport and quinidine. Cereport is an experimental drug, so forget that one for home testing, as well as the fact it is pretty expensive. The other is quinidine, an antiarrythmic drug at a dosage around 600-800mgs. This drug is a dangerous drug and has alot of unpleasant side effects, as well as being potentially deadly.
Tests have shown it to be reasonably effective in blocking P-glycoprotein.
situ experimental results revealed that the extent to which the intestinal absorption is affected by P-gp [?] was in the following order: quinidine > ritonavir > loperamide, verapamil, daunomycin > digoxin, cyclosporine A > dexamethasone, and vinblastine.
The slight problem with the P-glycoprotein blocking concept is that the drug loperamide is squeezing through the BBB by the "skin of it's teeth", meaning that absorption may be slow. This so far though seems to be the most effective way to get loperamide into the brain. There still may be another way that is better or perhaps combines this method with another one.
Mannitol: Mannitol may also be used to open the blood-brain barrier by temporarily shrinking the tightly coupled endothelial cells that make up the barrier. This makes mannitol indispensable for delivering various drugs directly to the brain (e.g. in the treatment of Alzheimer's disease). This method is defiantly in it's infancy.
Ascorbic acid: Apparently, the theory behind this is that ascorbic acid(despite the fact that it is very water soluble and non-lipid soluble)has a special transport system that allows it to enter the brain with relative ease and bypass the p-glycoprotein system. The concept is that if loperamide were bound to ascorbic acid to form an ascorbate-type compound, the body would then be able to transport loperamide to the brain via this system. This most likely can't be done by creating an ester with the alcohol on the loperamide molecule since ascorbic acid is not a carboxylic acid. It's acidic function it more complex.
The hydroxyls (OH) next to the bottom double bond are enols. One enol loses an electron pair, becoming an oxonium group (=OH+), by creating a double bond to the carbon. Simultaneously, the carbon-carbon double bond (between the enols) transfers its electrons to form a double bond to the next (two-oxygen) carbon. To give way, the double bond electrons of the carbonyl are received by the carbonyl's oxygen, to produce an enolate The oxonium promptly deprotonates to produce a carbonyl, and this loss of protons gives ascorbic acid its acidity. The overall reaction is enol deprotonation to produce an enolate, where the negative charge of the resulting enolate counterion is delocalized over the system of carbonyl (C=O) and the double bond (C=C). This delocalization makes the counterion more stable and less likely to regain the proton.
http://www.fileden.com/files/2007/1/10/623768/kingdxm%20pictures/500px-Ascorbic_acidity3.png
Attack of ascorbic enol on proton to give 1,3-diketone
Ascorbic acid also rapidly interconverts into two unstable diketone tautomers by proton transfer, although it is the most stable in the enol form. The proton of the enol is lost, and reacquired by electrons from the double bond, to produce a diketone. This is an enol reaction. There are two possible forms, 1,2-diketone and 1,3-diketone.
Anyway one would have to find a way to combine ascorbic acid and loperamide together. I am uncertian if simply making loperamide ascorbate(the salt form of the drug, as in loperamide hydrochloride) would work. It would be easy to make if it worked though.
One final note I would like to make: The fact that loperamide binds to P-glycoprotein may possibly be because of the amide linkage on it. The drug diphenoxylate has a very similar structure to loperamide and it is active. the diphenyl ring in loperamide probably doesn't have much to do with it not entering the brain since diphenxylate has the same diphenyl ring system. It has a carboxlate ethyl ester and a a
cyanide grouping, while loperamide has a hydroxyl alcohol and a dimethyl amide. esterfying loperamide(as I said before) could definatly help.
http://www.fileden.com/files/2007/1/10/623768/kingdxm%20pictures/loperamide.gif http://www.fileden.com/files/2007/1/10/623768/kingdxm%20pictures/diphenoxylate.gif
Loperamide ------------------- Diphenoxylate
Polysorbate-80 binding: this calls for binding this compound to loperamide so that it passes the BBB and a substance called P-glycoprotein(which I will mention later), and according to the reports it seems to have been reasonably affective. Unfortunately I doubt that anyone of us has the ability to duplicate this process, unless you have a lot of money and a sophisticated lab at home.
Oxidation of the hydroxyl molecule: I have heard talk of this one, sort of like oxidizing ephedrine to get methcathinone. Forget it. Oxidizing a tertiary alcohol is virtually impossible and even if you could do it, you would end up with a double bond somewhere in the vicinity of where the alcohol molecule was, possibly making a dangerous compound similar to MPTP. MPTP was a byproduct of the manufacture of a Demerol analog called MPPP. the MPTP caused almost instant advanced Parkinson's disease in the user, freezing them up like a statue. So of these people were found with the needles still stuck in their arms!!! Fuck that! And even if you didn't produce a dangerous by product what makes you think the drug would be active? Opiates need a quaternary carbon as part of their activity. The only exception to this rule is the fentanyl compounds(which have a nitrogen where the quaternary carbon would be), thiambutene(not used in the US), and salsolinol(a bicyclic form of dopamine, which activates opiate mu receptors but because of it's shape, it gets locked into the receptor, causing an antagonistic effect shortly after).
BTW, a quaternary carbon is a carbon atom that have 4 separate functional groups attached to it, causing it to have a chiral center. this is very important in opiate chemistry. Look at any opiate compound and you will find it(except gor the ones I stated above)
Reduction and dehalogenation: Again reduction will change the cirality of the Q-carbon, and besides do we really know if the alcohol has anything to do with it's BBB activity? There are so many lipid soluble portions to this drug that the alcoholic functional group should make very little difference in it's solubility in fatty tissue. Ephedrine penetrates the BBB, just not as good as methamphetamine. Besides, meth's higher affinity for dopamine receptors that ephedrine isn't just based on it's higher lipid solubility, but also in part due to it's closer resemblance to dopamine( due to the lack of the hydroxyl group). As far as dehalogenation goes, that is a question mark. The chlorine atom would make loperamide more lipid soluble than if it were replaced with a hydrogen atom. One thing I must say is that the chlorine and the alcohol may be the binding sites for P-glycoprotein on the loperamide molecule.
Acetylation: It is reasonable to say that an acetyl group(or even propionic acid) would make loperamide more fat soluble, but we don't know for sure that higher lipid solubility is what it needs. Either of these compounds may still have a high affinity for binding to P-glycoproteins, which is defiantly a big reason why loperamide doesn't enter the brain. Only serious experimentation in this area will reveal if this is effective.
Loperamide combined with P-glycoprotein-inhibiting drugs: This too has been tried with some success. Drugs such as Cereport, citalopram, fluoxetine, fluvoxamine, paroxetine, reboxetine, sertraline, venlafaxine, quinidine, ketoconazole, retonivir, cyclosporine A, and Erythromycin. Of the naturally occurring chemicals Curcumin, ginsenosides, piperine(from black pepper), some catechins from green tea, and silymarin from milk thistle were found to be inhibitors of Pgp, while some catechins from green tea increased Pgp-mediated drug transport by heterotropic allosteric mechanism, and St. John's wort induced the intestinal expression of Pgp in vitro and in vivo. Some components (e.g., bergamottin and quercetin) from grapefruit juice were reported to modulate Pgp activity.
Personally I have tried quercerin(found in good concentrations in grapefruit) and found it to be ineffective. Of all of these, the only ones I have found on the web to have been effective in testing was Cereport and quinidine. Cereport is an experimental drug, so forget that one for home testing, as well as the fact it is pretty expensive. The other is quinidine, an antiarrythmic drug at a dosage around 600-800mgs. This drug is a dangerous drug and has alot of unpleasant side effects, as well as being potentially deadly.
Tests have shown it to be reasonably effective in blocking P-glycoprotein.
situ experimental results revealed that the extent to which the intestinal absorption is affected by P-gp [?] was in the following order: quinidine > ritonavir > loperamide, verapamil, daunomycin > digoxin, cyclosporine A > dexamethasone, and vinblastine.
The slight problem with the P-glycoprotein blocking concept is that the drug loperamide is squeezing through the BBB by the "skin of it's teeth", meaning that absorption may be slow. This so far though seems to be the most effective way to get loperamide into the brain. There still may be another way that is better or perhaps combines this method with another one.
Mannitol: Mannitol may also be used to open the blood-brain barrier by temporarily shrinking the tightly coupled endothelial cells that make up the barrier. This makes mannitol indispensable for delivering various drugs directly to the brain (e.g. in the treatment of Alzheimer's disease). This method is defiantly in it's infancy.
Ascorbic acid: Apparently, the theory behind this is that ascorbic acid(despite the fact that it is very water soluble and non-lipid soluble)has a special transport system that allows it to enter the brain with relative ease and bypass the p-glycoprotein system. The concept is that if loperamide were bound to ascorbic acid to form an ascorbate-type compound, the body would then be able to transport loperamide to the brain via this system. This most likely can't be done by creating an ester with the alcohol on the loperamide molecule since ascorbic acid is not a carboxylic acid. It's acidic function it more complex.
The hydroxyls (OH) next to the bottom double bond are enols. One enol loses an electron pair, becoming an oxonium group (=OH+), by creating a double bond to the carbon. Simultaneously, the carbon-carbon double bond (between the enols) transfers its electrons to form a double bond to the next (two-oxygen) carbon. To give way, the double bond electrons of the carbonyl are received by the carbonyl's oxygen, to produce an enolate The oxonium promptly deprotonates to produce a carbonyl, and this loss of protons gives ascorbic acid its acidity. The overall reaction is enol deprotonation to produce an enolate, where the negative charge of the resulting enolate counterion is delocalized over the system of carbonyl (C=O) and the double bond (C=C). This delocalization makes the counterion more stable and less likely to regain the proton.
http://www.fileden.com/files/2007/1/10/623768/kingdxm%20pictures/500px-Ascorbic_acidity3.png
Attack of ascorbic enol on proton to give 1,3-diketone
Ascorbic acid also rapidly interconverts into two unstable diketone tautomers by proton transfer, although it is the most stable in the enol form. The proton of the enol is lost, and reacquired by electrons from the double bond, to produce a diketone. This is an enol reaction. There are two possible forms, 1,2-diketone and 1,3-diketone.
Anyway one would have to find a way to combine ascorbic acid and loperamide together. I am uncertian if simply making loperamide ascorbate(the salt form of the drug, as in loperamide hydrochloride) would work. It would be easy to make if it worked though.
One final note I would like to make: The fact that loperamide binds to P-glycoprotein may possibly be because of the amide linkage on it. The drug diphenoxylate has a very similar structure to loperamide and it is active. the diphenyl ring in loperamide probably doesn't have much to do with it not entering the brain since diphenxylate has the same diphenyl ring system. It has a carboxlate ethyl ester and a a
cyanide grouping, while loperamide has a hydroxyl alcohol and a dimethyl amide. esterfying loperamide(as I said before) could definatly help.
http://www.fileden.com/files/2007/1/10/623768/kingdxm%20pictures/loperamide.gif http://www.fileden.com/files/2007/1/10/623768/kingdxm%20pictures/diphenoxylate.gif
Loperamide ------------------- Diphenoxylate