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haidut

haidut

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Presumably your product is not metabolized by N-acetylation since it does not have an amino group?

None of them really get metabolized much, neither adamantane nor its derivatives.
The Lipophilic Bullet Hits the Targets: Medicinal Chemistry of Adamantane Derivatives
"...In addition, the rigid hydrocarbon protects functional groups in its proximity from metabolic cleavage, enhancing duration of action of, amongst others, peptide-derived drugs. On the other hand, it is “biocompatible”, as metabolism can take place in the liver, so that toxic effects by accumulation upon chronic treatment are not to be expected. Most adamantane-based drugs for which metabolites have been studied are, in fact, being excreted largely unmodified, which has the added benefit that possible side effects arising from bioactive metabolites are intrinsically improbable."

The review on liphophilicity and adamantane derivatives posted in the original post has a section on metabolism where it says that the adamantane cage is excreted in changed.
"...What happens to the adamantane-derived pharmaceuticals once they have been administered? In this final chapter, we will briefly discuss metabolic degradation of some drugs incorporating adamantane as a building block. In mice, most of the amantadine dose given has been found to be excreted unchanged with urine within 12 hours after oral application.848 About 2% of the drug can be found in feces, so there is good oral absorption. Some metabolism does occur as still part of the dose cannot be collected in the animal's urine and feces. In rats, recovery of amantadine was lower; likewise, in dogs only 19% of the drug could be recovered from urine. N-methylation occurs in dog, as in this species, ~10% of the excreted amantadine is actually metabolized to 213 (Scheme 61). In monkeys, the half-life of the drug is ~5 h, and some metabolic conversions do also occur. This report also stated that in man ~86% of the drug can be recovered from urine, and there was no evidence of acylated, methylated, or otherwise modified amantadine metabolites in any of the urine samples from humans that were analyzed by GLC."

"...However, after analyzing samples from an individual attempting suicide by taking very large amounts of the drug indicating that metabolic conversions do occur in humans, the metabolism of amantadine under therapeutic dose regimens was revisited.849 When taking 200 mg orally, still the vast majority of amantadine (65–85%) can be detected in urine. The major metabolite in urine was acetylated 432, 5–15% were found in urine. A total of eight metabolites could be identified; all of which incorporated an unmodified adamantane moiety."
 
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Name1

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Let me search through my notes. It's been a while since I looked at that link. I am pretty sure I emailed the authors about unsubstituted adamantane and they said it was also inhibitory. As far as I remember, this is one of the studies they sent me. I know it's still not pure adamantane, so I will find their email and post it here.
Neuropsychopharmacology - Novel Neuroprotective Mechanisms of Memantine: Increase in Neurotrophic Factor Release from Astroglia and Anti-Inflammation by Preventing Microglial Activation
"...Thus, we determined whether the HDAC activity is affected in the cellular levels of astroglia treated with memantine (10 μM). ANOVA analysis showed a significant main effect among these groups (F(5, 12)=28.95, p<0.001) (Figure 4b). The cellular HDAC activity in memantine-treated astroglia was significantly suppressed at 2 h (t=5.73, p<0.01), maximally at 4 h (t=10.77, p<0.001), and at 12 h (t=5.37, p<0.01), compared with the controls with post hoc analysis (Figure 4b). We also compared the effects of VAP (1 mM), a widely used HDAC inhibitor, and memantine (10 μM) on the HDAC activity of astroglia at 4 h after administration. The activity was almost equipotently inhibited about 30% by either memantine or VPA (t=0.43, p>0.5, Student's t-test). These results indicate that memantine and VPA inhibited HDAC activity in different mechanisms. Therefore, we examined whether changes of histone acetylation levels occur at the GDNF promoter region by ChIP study. The result showed that markedly enhanced association of acetylated H4 for one (Pc) (F(2, 6)=66.33, p<0.001, Figure 4c) out of these three primer set regions was observed in the memantine-treated astroglia. Post hoc analysis showed that the levels of acetylation of Pc region were significantly increased at 1 h (t=6.48, p<0.05), and 4 h (t=11.49, p<0.001) (Figure 4c), indicating that memantine triggered recruitment of acetylated histone, specifically to the proximally close to the initiator site of GDNF gene."

Also, a lot of the rationale for using unsubsituted adamantane as the actual supplement comes from this extensive review below, which I posted in the original thread. That review focuses on the parent compound - the unsubstituted adamantane, and it various properties and benefits. It concludes that it is the adamantane itself, and not its various modifications, that is responsible for the plethora of benefits observed with all of those chemical derivatives.
The Lipophilic Bullet Hits the Targets: Medicinal Chemistry of Adamantane Derivatives
"...We will not elaborate on the development of pharmaceuticals from oxaadamantanes, azaadamantanes, or any other heteroadamantanes, that could be viewed as inspired by natural products. There are, however, also natural products that incorporate the adamantane skeleton,1921 some of which also display interesting biological properties. This review focuses on the medicinal chemistry of the parent hydrocarbon, adamantane, and its derivatives. "

Can you show me a single quote from the Wanka et al review which actually discusses the medicinal effects of unsubstituted adamantane (C10H16)? Or show me a single one of the 871 studies referenced which measured the medicinal effects of unsubstituted adamantane (C10H16)?
 

ThinkPerceive

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To what did he attribute the cause of the positive effects of the frenectomy?

Must be individual? She was positively glowing - I almost wanted to run out and get one just in case.

I think the most obvious difference for her was balance. She said she had been a lifelong klutz - suddenly her balance was much better. Even her vision got better. And there were emotional improvements too.

I've been hoping to run into her, to learn how it's been since I spoke with her.
 
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haidut

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Can you show me a single quote from the Wanka et al review which actually discusses the medicinal effects of unsubstituted adamantane (C10H16)? Or show me a single one of the 871 studies referenced which measured the medicinal effects of unsubstituted adamantane (C10H16)?

Here are some. There are studies on unmodified adamantane but most of them were published in the 1960s and are not available online so I will have to scan a few and post here. My take is that adamantane's main beneficial effect is structural - i.e. it has effects on the cell akin to saturated fat with few direct effects on receptors, channels or enzymes - and is very basic. It makes the cell extremely hydrophobic and as such reduces its sensitivity to estrogen, PUFA, serotonin and variety of other stressors like viruses and bacteria. The most recent studies on amantadine and rimantadine found the same - i.e. their antiviral effects are due to improved structural stability and it is the adamantane core providing that effect (not the amino or methyl groups). One of the quotes below actually hints at that as well even though the review was published years before the latest study on amantadine's antiviral effects. But adamantane does have direct effects on viruses, ion channels, and even some "receptors".

1. "...The (hetero)adamantane scaffold might play a decisive role in the three-dimensional adjustment of the pharmacophors of the abovementioned natural products and natural-product inspired compounds. It is clear that the sheer activity of a drug, exerted by the fit into a receptor's binding pocket, the active site, is essentially triggered by this three-dimensional structure. This has historically been described as the “key-lock” principle and nowadays carries the moniker “induced fit”, expressing a more dynamic understanding of the receptor-ligand interactions."

2. "...More recent examples for the “add-on” strategy of modifications of a primary pharmacophor with the adamantane “lipophilic bullet” acting as a functional subunit, sometimes more suitably described as a “secondary pharmacophor”, include glycolipids."

3. "...Taken together, these early findings supported a concept of the amino group acting as a primary pharmacophor that is assisted by an (preferably unsubstituted) adamantane cage in the appropriate distance, acting as a secondary pharmacophor – both leading to pronounced anti-Influenza A activity in a synergistic manner."

4. "...The smaller bis-noradamantanes were less potent. The numerous amino derivatives of adamantane and some other polycyclic hydrocarbon cages (related in shape and size) screened to date, some of which we have presented herein to summarize four decades of SAR, demonstrate that the two co-pharmacophores (bulky hydrocarbon and amino group) have to be optimized to gain best potency."

5. "...Strikingly, originating from amantadine resistance, structure-based design of novel cage amines to tackle this challenge at first led away from the adamantane motif, only to find novel adamantane derivatives such as 109 a few years later that are capable to inhibit Influenza A replication, at least in in vitro assays."

6. "...These pore-lining hydrophilic residues would reduce the affinity of the pore for binding to the lipophilic cage hydrocarbon moieties of the aminoadamantane antivirals amantadine and rimantadine, at the same time enhancing the proton channel activity."

7. "...However, the structural and mechanistic insights gained for the M2 channel and its blocking through the aminoadamantanes has shown to offer opportunities to design new drugs that target M2, in particular, of “adamantane-resistant”218 strains. Oddly enough, this research –again– gave adamantane derivatives such as 109 as optimized lead structures. "

8. "...As mentioned before as well as in chapter 4.1.1, novel aminoadamantanes are frequently being screened in HSV assays as well, but no spectacular insights, other than mounting evidence for tromantadine's sidechain and the lipophilic adamantane moiety being equally important for anti-HSV potency, have been reported."

9. "...The library of adamantane derivatives studied was greatly expanded in subsequent work that was also directed towards identifying the mechanism of action of these compounds.238 The similar potency of the active compounds against multiple responses in different cell types suggests a highly conserved target integral to the cells that have been utilized, probably the Golgi or the endoplasmatic reticulum. The active structures had a strong preference for terminal large lipophilic groups, e. g., adamantane moieties."

10. "...Combining the anti-HIV pharmacophores phthalimide (vide supra), adamantane, and AZT, the AZT prodrug candidate 142 was identified as showing considerably increased anti-HIV potency when compared to the analog without the adamantane modification (EC50 = 0.06 – 0.11 μM);

11. "...This time, the steroid pharmacophor has been replaced by adamantane. Cosalane and several derivatives, e.g. “Cosalog 25” (144) also displayed significant inhibitory activity against HIV-1 protease and HIV-1 integrase.296 While 144 (IC50 = 7 μM) was not as potent as the best analogues screened, it had a higher potency than cosalane itself. It also inhibited HIV-1 protease in vitro (IC50 = 0.37 μM) approximately four times stronger than cosalane."

12. "...The anti-HIV activity in cell culture was reflected, at least in part, by the inhibitory profile of the compounds against recombinant HIV reverse transcriptase (IC50 ((R)-146) = (19 ± 11) μM; IC50 (147) ≥ 900 μM. In other words, this novel class of NNRTIs obligatorily requires adamantane as a co-pharmacophore for activity."

13. "...Compounds screened in this work with spirocyclopentane- or spirocyclohexanetrioxane groups were generally less active. Once more, the adamantane motif proved to enhance activity of the spiroannelated malaria chemotherapeutics."

14. "...Likewise, the adamantane motif is required for strong antimalarial activity or more generally, lipophilic antimalarial peroxides are potent....Lipophilic moieties other than adamantane were not as active, 170 and 171 were only weakly potent in vitro and completely inactive in vivo, while similarly lipophilic spiroadamantane 172 was significantly more active."

15. "...While lipophilicity was found to contribute positively to the antiparkinsonian activity of the aminoadamantanes, it clearly is not the sole activity-determining factor, at least in the class of the aminoadamantanes. The workers stated that a factor best describing the observed activity trends would be “molecular shape”."

16. "... The adamantane and the terminal ammonium group were postulated to interact with a lipophilic and a nucleophilic site, which were assumed to be separated by ~ 10 Å in the AMPAR, but close to one another in the NMDAR, thereby explaining, at least in part, the selectivity of the dications for the AMPAR."

17. "...The adamantylated estradiol 320 is a non-receptor binding estrogen analogue that has been found to display neuroprotective properties through a decrease of glutamate-induced excitotoxicity – for therapeutic applications, this seems interesting as androgen effects of neuroprotective compounds are certainly not desirable." (Note: estrogen increases glutamate-induces excitotoxicity, so the only possible explanation of the above effect is through the adamantane group functioning as an NMDA antagonist, which has been confirmed beyond doubt).

18. "...Based on a cell-based high-throughput-screening in 96-well format, adamantane bisamide 323 (Scheme 47) was identified as a “hit”. However, this molecule was considered too large and too lipophilic, so “hit-to-lead-studies” have been performed.643 Notably, no replacement for the adamantane moiety was found."

19. "...What makes this globular paraffine so special? First of all, size matters: To hit targets like ion channels, adamantane and some methyl substituted derivatives obviously have the appropriate molecular dimensions to functionally block the conductance of viroporins or calcium channels. Secondly, lipophilicity has a direct effect on affinity in several cases, but also an indirect one, enhancing CNS-access through facilitated penetration of the blood-brain-barrier. Lipophilicity is also beneficial for test drugs to hit targets in membranes, in particular, in lipid rafts. In addition, the rigid hydrocarbon protects functional groups in its proximity from metabolic cleavage, enhancing duration of action of, amongst others, peptide-derived drugs. On the other hand, it is “biocompatible”, as metabolism can take place in the liver, so that toxic effects by accumulation upon chronic treatment are not to be expected."
 
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Name1

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Here are some. There are studies on unmodified adamantane but most of them were published in the 1960s and are not available online so I will have to scan a few and post here. My take is that adamantane's main beneficial effect is structural - i.e. it has effects on the cell akin to saturated fat with few direct effects on receptors, channels or enzymes - and is very basic. It makes the cell extremely hydrophobic and as such reduces its sensitivity to estrogen, PUFA, serotonin and variety of other stressors like viruses and bacteria. The most recent studies on amantadine and rimantadine found the same - i.e. their antiviral effects are due to improved structural stability and it is the adamantane core providing that effect (not the amino or methyl groups). One of the quotes below actually hints at that as well even though the review was published years before the latest study on amantadine's antiviral effects. But adamantane does have direct effects on viruses, ion channels, and even some "receptors".

"...The (hetero)adamantane scaffold might play a decisive role in the three-dimensional adjustment of the pharmacophors of the abovementioned natural products and natural-product inspired compounds. It is clear that the sheer activity of a drug, exerted by the fit into a receptor's binding pocket, the active site, is essentially triggered by this three-dimensional structure. This has historically been described as the “key-lock” principle and nowadays carries the moniker “induced fit”, expressing a more dynamic understanding of the receptor-ligand interactions."

"...More recent examples for the “add-on” strategy of modifications of a primary pharmacophor with the adamantane “lipophilic bullet” acting as a functional subunit, sometimes more suitably described as a “secondary pharmacophor”, include glycolipids."

"...Taken together, these early findings supported a concept of the amino group acting as a primary pharmacophor that is assisted by an (preferably unsubstituted) adamantane cage in the appropriate distance, acting as a secondary pharmacophor – both leading to pronounced anti-Influenza A activity in a synergistic manner."

"...The smaller bis-noradamantanes were less potent. The numerous amino derivatives of adamantane and some other polycyclic hydrocarbon cages (related in shape and size) screened to date, some of which we have presented herein to summarize four decades of SAR, demonstrate that the two co-pharmacophores (bulky hydrocarbon and amino group) have to be optimized to gain best potency."

"...Strikingly, originating from amantadine resistance, structure-based design of novel cage amines to tackle this challenge at first led away from the adamantane motif, only to find novel adamantane derivatives such as 109 a few years later that are capable to inhibit Influenza A replication, at least in in vitro assays."

"...These pore-lining hydrophilic residues would reduce the affinity of the pore for binding to the lipophilic cage hydrocarbon moieties of the aminoadamantane antivirals amantadine and rimantadine, at the same time enhancing the proton channel activity."

"...However, the structural and mechanistic insights gained for the M2 channel and its blocking through the aminoadamantanes has shown to offer opportunities to design new drugs that target M2, in particular, of “adamantane-resistant”218 strains. Oddly enough, this research –again– gave adamantane derivatives such as 109 as optimized lead structures. "

"...As mentioned before as well as in chapter 4.1.1, novel aminoadamantanes are frequently being screened in HSV assays as well, but no spectacular insights, other than mounting evidence for tromantadine's sidechain and the lipophilic adamantane moiety being equally important for anti-HSV potency, have been reported."

"...The library of adamantane derivatives studied was greatly expanded in subsequent work that was also directed towards identifying the mechanism of action of these compounds.238 The similar potency of the active compounds against multiple responses in different cell types suggests a highly conserved target integral to the cells that have been utilized, probably the Golgi or the endoplasmatic reticulum. The active structures had a strong preference for terminal large lipophilic groups, e. g., adamantane moieties."

"...Combining the anti-HIV pharmacophores phthalimide (vide supra), adamantane, and AZT, the AZT prodrug candidate 142 was identified as showing considerably increased anti-HIV potency when compared to the analog without the adamantane modification (EC50 = 0.06 – 0.11 μM);

"...This time, the steroid pharmacophor has been replaced by adamantane. Cosalane and several derivatives, e.g. “Cosalog 25” (144) also displayed significant inhibitory activity against HIV-1 protease and HIV-1 integrase.296 While 144 (IC50 = 7 μM) was not as potent as the best analogues screened, it had a higher potency than cosalane itself. It also inhibited HIV-1 protease in vitro (IC50 = 0.37 μM) approximately four times stronger than cosalane."

"...The anti-HIV activity in cell culture was reflected, at least in part, by the inhibitory profile of the compounds against recombinant HIV reverse transcriptase (IC50 ((R)-146) = (19 ± 11) μM; IC50 (147) ≥ 900 μM. In other words, this novel class of NNRTIs obligatorily requires adamantane as a co-pharmacophore for activity."

"...Compounds screened in this work with spirocyclopentane- or spirocyclohexanetrioxane groups were generally less active. Once more, the adamantane motif proved to enhance activity of the spiroannelated malaria chemotherapeutics."

"...Likewise, the adamantane motif is required for strong antimalarial activity or more generally, lipophilic antimalarial peroxides are potent....Lipophilic moieties other than adamantane were not as active, 170 and 171 were only weakly potent in vitro and completely inactive in vivo, while similarly lipophilic spiroadamantane 172 was significantly more active."

"...While lipophilicity was found to contribute positively to the antiparkinsonian activity of the aminoadamantanes, it clearly is not the sole activity-determining factor, at least in the class of the aminoadamantanes. The workers stated that a factor best describing the observed activity trends would be “molecular shape”."

"... The adamantane and the terminal ammonium group were postulated to interact with a lipophilic and a nucleophilic site, which were assumed to be separated by ~ 10 Å in the AMPAR, but close to one another in the NMDAR, thereby explaining, at least in part, the selectivity of the dications for the AMPAR."

"...The adamantylated estradiol 320 is a non-receptor binding estrogen analogue that has been found to display neuroprotective properties through a decrease of glutamate-induced excitotoxicity – for therapeutic applications, this seems interesting as androgen effects of neuroprotective compounds are certainly not desirable." (Note: estrogen increases glutamate-induces excitotoxicity, so the only possible explanation of the above effect is through the adamantane group functioning as an NMDA antagonist, which has been confirmed beyond doubt).

"...Based on a cell-based high-throughput-screening in 96-well format, adamantane bisamide 323 (Scheme 47) was identified as a “hit”. However, this molecule was considered too large and too lipophilic, so “hit-to-lead-studies” have been performed.643 Notably, no replacement for the adamantane moiety was found."

"...What makes this globular paraffine so special? First of all, size matters: To hit targets like ion channels, adamantane and some methyl substituted derivatives obviously have the appropriate molecular dimensions to functionally block the conductance of viroporins or calcium channels. Secondly, lipophilicity has a direct effect on affinity in several cases, but also an indirect one, enhancing CNS-access through facilitated penetration of the blood-brain-barrier. Lipophilicity is also beneficial for test drugs to hit targets in membranes, in particular, in lipid rafts. In addition, the rigid hydrocarbon protects functional groups in its proximity from metabolic cleavage, enhancing duration of action of, amongst others, peptide-derived drugs. On the other hand, it is “biocompatible”, as metabolism can take place in the liver, so that toxic effects by accumulation upon chronic treatment are not to be expected."

None of these quotes discuss the medicinal effects of unsubstituted adamantane (C10H16), they all discuss the important role that the adamantane scaffold or adamantane moiety plays within certain compounds (much like how methyl or phenyl groups play an important role within many compounds), as you would expect in a review of the medicinal chemistry of adamantane derivatives. Can you post references for the studies from the sixties which measure the medicinal effects of unsubstituted adamantane (C10H16), i.e. what is in Diamant, and the most recent studies on amantadine and rimantadine that you mention above? Thanks
 
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haidut

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None of these quotes discuss the medicinal effects of unsubstituted adamantane (C10H16), they all discuss the important role that the adamantane scaffold or adamantane moiety plays within certain compounds (much like how methyl or phenyl groups play an important role within many compounds), as you would expect in a review of the medicinal chemistry of adamantane derivatives. Can you post references for the studies from the sixties which measure the medicinal effects of unsubstituted adamantane (C10H16), i.e. what is in Diamant? Thanks

Yes, I will post those studies when I get them. I think you are brushing aside those quotes too quickly. You said the following:

Can you show me a single quote from the Wanka et al review which actually discusses the medicinal effects of unsubstituted adamantane (C10H16)

Pretty much all of the quotes I provided refer to the fact that the core adamantane group has specific properties like ion channel blocking and anti-viral effects. That is the whole point of that review study - to point out the role of the core adamantane group in the effects of these composite drugs that contain the adamantane core. I get your point about direct studies with unsubstituted adamantane, and I will post them when I locate and scan them. But that review does address at least one of your concerns - whether the adamantane itself has medicinal properties. According to that review, it does.
 
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Name1

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Yes, I will post those studies when I get them. I think you are brushing aside those quotes too quickly. You said the following:



Pretty much all of the quotes I provided refer to the fact that the core adamantane group has specific properties like ion channel blocking and anti-viral effects. That is the whole point of that review study - to point out the role of the core adamantane group in the effects of these composite drugs that contain the adamantane core. I get your point about direct studies with unsubstituted adamantane, and I will post them when I locate and scan them. But that review does address at least one of your concerns - whether the adamantane itself has medicinal properties. According to that review, it does.


"...Taken together, these early findings supported a concept of the amino group acting as a primary pharmacophor that is assisted by an (preferably unsubstituted) adamantane cage in the appropriate distance, acting as a secondary pharmacophor – both leading to pronounced anti-Influenza A activity in a synergistic manner."


This quote indicates that the authors think that the amino group is the 'primary pharmacophor', and the preceding line says that:

'Replacing the amino group in amantadine with other functional groups like –OH, –SH, –CN, –CO2H, –Cl, or –Br gave inactive compounds.'

Why would this be the case if the adamantane group is responsible for the anti-viral activity of amantadine?

And feel free to just post the references, I should be able to find the studies. Thanks
 

Velve921

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Thanks for the report. I personally do not use more than 10mg at once and repeat if needed a few times daily. I really like the sleep effects from 10mg before bed as at the lower dose it should be primarily anti-excitotoxic and anti-cortisol and so much dopaminergic and and simulating enough to disrupt sleep.

Thus far, cyproheptadine and androsterone have shown the best sleep effect I've personally had thus far, is there any reason to believe that this could have stronger effects for sleep? Or better yet, could it be sleep supportive by design?
 
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"...Taken together, these early findings supported a concept of the amino group acting as a primary pharmacophor that is assisted by an (preferably unsubstituted) adamantane cage in the appropriate distance, acting as a secondary pharmacophor – both leading to pronounced anti-Influenza A activity in a synergistic manner."


This quote indicates that the authors think that the amino group is the 'primary pharmacophor', and the preceding line says that:

'Replacing the amino group in amantadine with other functional groups like –OH, –SH, –CN, –CO2H, –Cl, or –Br gave inactive compounds.'

Why would this be the case if the adamantane group is responsible for the anti-viral activity of amantadine?

And feel free to just post the references, I should be able to find the studies. Thanks

A little later they said that reintroduction of the adamantane group restore antiviral activity, albeit with the addition of other active groups. So, the adamantane group seems to be play a vital role and that is why they call it a secondary pharmacophore. I don't know for sure why but here is my take.
Viral entry into the cell depends on cell affinity for water and presence of estrogen (estrogen entry into the cell also depends on affinity of cell for water). It is not a coincidence that estrogen activates retroviruses and promotes the virulence of "regular" viruses like the common cold, norovirus or the herpes simplex family. Chemicals that change the cell affinity for water (i.e.make it more lipophillic) like tocopherol, progesterone, saturated fat, fully reduced steroids like DHT/androsterone/5a-DHP, etc all have anti-viral effects. They all happen to oppose estrogen as well. The problem with these chemicals is that they undergo extensive metabolism and you have to take high doses for a long time to change the systemic affinity for water. Adamantane is unique among all of these precisely because it does not undergo much metabolism. It just gets in the cell and stays there. The link I posted on one of the steroid adamantane conjugates called Bolmantalate (testosterone-adamantane complex) show a half life of 4-6 weeks as opposed to a few hours. So, I would venture a guess that adamantane is really good at making the cell resistant to the entrance of estrogen by making the entire cell very lipophillic and making these effects last days, if not weeks. There is also evidence that adamantane derivatives lower cellular pH, which also has strong antiviral effect. The amino group has the same effect on pH and this is probably its primary anti-viral effect. Ammonia "loading" (or even using urea) has been used for treating severe viral infections in the past. There is evidence that the hyperammonemia state often seen in hepatitis and other viral infections is an adaptation with an anti-viral goal. But I digress.
A more liphophillic intracellular environment inhibits both the binding of the estrogen to the ER and its translocation to the nucleus. So, the overall effects of adamantane would be functional estrogen antagonism as a result of structural water change, change in cellular pH and change in affinity for water. That is probably the main cause behind its anti-viral effects you mentioned, and also its anti-excitoxic, anti-serotonin, anti-histamine, and anticholinergic effects. The NMDA receptor, histamine, and the cholinergic system are the main mediators of estrogen's effects inside the cell (as Peat has mentioned many times) and the adamantane derivatives have been shown to oppose all of these without any direct interaction. Memantine is marketed as an NMDA antagonist but there is no evidence that it actually binds to and antagonizes that receptor. Same for the opposition to glutamate, acetylcholine and promotion of dopaminergic activity - i.e. none of these have been shown to be directly engaged by any of the adamantane derivatives. I think this is one of the reasons we are not seeing more human trials and approvals - there is no clearly established genomic mechanism of action for any of the adamantane derivatives, and pharma companies do not like to sell a chemical whose mechanism of action is a mysterious "stabilization" of the cell (not sure if they even accept such process to exist). Perhaps more importantly, if adamantane and its derivatives are indeed functional anti-estrogens then this will make them even less palatable to the pharma shills.

Estrogens and infection. - PubMed - NCBI
"...Current information indicates that estrogens may depress cell-mediated immunity, impair the activity of natural killer cells, and suppress some aspects of neutrophil function. Estrogens potentiate the production of systemic antibody, but local antibody responses may be impaired."

Estrogen Mediates Innate and Adaptive Immune Alterations to Influenza Infection in Pregnant Mice
"...We conclude that elevated estrogen levels result in an attenuated anti-viral immune response, and that pregnancy-associated morbidities occur in the context of this anti-inflammatory phenotype."

17-beta estradiol promotion of herpes simplex virus type 1 reactivation is estrogen receptor dependent. - PubMed - NCBI
"...In a murine HSV-1 corneal infection model, we establish 17-beta estradiol (17-betaE) treatment of latently infected ovariectomized mice induces viral reactivation, as demonstrated by increased viral load and increased immediate-early viral gene expression in the latently infected trigeminal ganglia (TG). Interestingly, the increased HSV reactivation occurred in the absence of inhibition of viral specific CD8(+) T-cell effector function. 17-betaE administration increased HSV reactivation in CD45(+) cell-depleted TG explant cultures, providing further support that leukocyte-independent effects on latently infected neurons were responsible for the increased reactivation. The drug-induced increases in HSV copy number were not recapitulated upon in vivo treatment of latently infected estrogen receptor alpha-deficient mice, evidence that HSV reactivation promoted by 17-betaE was estrogen receptor dependent."

Herpes and Other Genitourinary Infections, and Gastroschisis and Oestrogen
"...A number of gastroschisis risk factors involve increased maternal oestrogen levels, presumably acting as a predisposition to fetal thrombosis.2 At the same time, clinical and laboratory evidence supports latent herpes simplex reactivation by oestrogen.3 Therefore, gastroschisis and genital herpes (+/– medication) could both be related to high maternal oestrogen levels, explaining their association."
 
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Thus far, cyproheptadine and androsterone have shown the best sleep effect I've personally had thus far, is there any reason to believe that this could have stronger effects for sleep? Or better yet, could it be sleep supportive by design?

I don't think it has any direct sleep inducing effects. It is not sedating like cypro and androsterone. The best I can describe it is profound sense of relaxation, which enables people to fall asleep. A different mechanism but it should still help with sleep.
 

ThinkPerceive

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I don't think it has any direct sleep inducing effects. It is not sedating like cypro and androsterone. The best I can describe it is profound sense of relaxation, which enables people to fall asleep. A different mechanism but it should still help with sleep.

I've been taking this before bed, and don't notice increased sleepiness (or wakefulness). I might sleep a little better - but if I do it's subtle.
 
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I've been taking this before bed, and don't notice increased sleepiness (or wakefulness). I might sleep a little better - but if I do it's subtle.

Any other effects you may have noticed? More energy, mood improvement, muscle strength, etc?
 

Velve921

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I don't think it has any direct sleep inducing effects. It is not sedating like cypro and androsterone. The best I can describe it is profound sense of relaxation, which enables people to fall asleep. A different mechanism but it should still help with sleep.

Thanks for the response!
 

ThinkPerceive

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Any other effects you may have noticed? More energy, mood improvement, muscle strength, etc?

Maybe some mood stability? I do seem slightly more productive - and I'll happily take even slight improvement there. But I'm one of those people who has almost no response to anything. For me, "subtle" is about as big as it gets. I've had the same response to all of your (excellent) products so far, and take most of them on faith.

That said it's likely there IS a physiologic response - I just don't feel it. I once took 300ug T3 daily for some months (yes, I'm crazy) and got NOTHING from it - until my normally high cholesterol dropped to way below reference and I started having problems from that.
 
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haidut

haidut

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Maybe some mood stability? I do seem slightly more productive - and I'll happily take even slight improvement there. But I'm one of those people who has almost no response to anything. For me, "subtle" is about as big as it gets. I've had the same response to all of your (excellent) products so far, and take most of them on faith.

That said it's likely there IS a physiologic response - I just don't feel it. I once took 300ug T3 daily for some months (yes, I'm crazy) and got NOTHING from it - until my normally high cholesterol dropped to way below reference and I started having problems from that.

Wow, 300mcg T3 is a lot! What were the symptoms of your low cholesterol?
 

Name1

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A little later they said that reintroduction of the adamantane group restore antiviral activity, albeit with the addition of other active groups. So, the adamantane group seems to be play a vital role and that is why they call it a secondary pharmacophore.

This is the quote that I posted:

'Replacing the amino group in amantadine with other functional groups like –OH, –SH, –CN, –CO2H, –Cl, or –Br gave inactive compounds. Taken together, these early findings supported a concept of the amino group acting as a primary pharmacophor that is assisted by an (preferably unsubstituted) adamantane cage in the appropriate distance, acting as a secondary pharmacophor – both leading to pronounced anti-Influenza A activity in a synergistic manner.'

Where do they discuss removing the adamantane group (in this quote)? How can the adamantane group be reintroduced if it hasn't been removed?
 
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haidut

haidut

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This is the quote that I posted:

'Replacing the amino group in amantadine with other functional groups like –OH, –SH, –CN, –CO2H, –Cl, or –Br gave inactive compounds. Taken together, these early findings supported a concept of the amino group acting as a primary pharmacophor that is assisted by an (preferably unsubstituted) adamantane cage in the appropriate distance, acting as a secondary pharmacophor – both leading to pronounced anti-Influenza A activity in a synergistic manner.'

Where do they discuss removing the adamantane group (in this quote)? How can the adamantane group be reintroduced if it hasn't been removed?

Like I said, later in the study they talk about the removal and then re-addition of the adamantane group. Look at quotes #5 and #7. It's still in the context of anti-viral activity, which is what your quote discusses.

The underlined portions of the quotes I posted, and especially the parts in read clearly show that the authors of that study consider the adamantane group to be a pharmacophore, and in some cases a required one for observed effects. Quotes #8, #10, #11, #12, #14, and even #18, and #19 are such examples.
 

Mufasa

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Took it for 2 days.

My digestive issues I had since I was on holiday (eating standard Moroccan diet with lots of bread) cleared up. I'm back from holiday for a week, could be just coincidence. But I had a very large good stool, only 30 min after waking up. I can't remember if I have ever had a stool that early.

Something in my says/hopes that this stuff does something exactly what I need. I'm diagnosed ADD, I have my symptoms under control quite well, if I live very healthy, but for example in this holiday, when there are so much stressors, like unhealthy diet, sunburned, standard commercial suncream that makes me feel itched etc. etc. I was getting back into my very ADD self. Forgetting stuff in places, (like my wallet ...). Very unorganised. Dreamy. Not able to focus on conversations etc.

But I keep my fingers crossed. I had the whole day a very clear mind. Normally, it takes me weeks of dedicated healthy stressless living (peat diet, yoga, sunshine etc.) to get this kind of mind.

Very eager to experiment more with this.
 
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haidut

haidut

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Took it for 2 days.

My digestive issues I had since I was on holiday (eating standard Moroccan diet with lots of bread) cleared up. I'm back from holiday for a week, could be just coincidence. But I had a very large good stool, only 30 min after waking up. I can't remember if I have ever had a stool that early.

Something in my says/hopes that this stuff does something exactly what I need. I'm diagnosed ADD, I have my symptoms under control quite well, if I live very healthy, but for example in this holiday, when there are so much stressors, like unhealthy diet, sunburned, standard commercial suncream that makes me feel itched etc. etc. I was getting back into my very ADD self. Forgetting stuff in places, (like my wallet ...). Very unorganised. Dreamy. Not able to focus on conversations etc.

But I keep my fingers crossed. I had the whole day a very clear mind. Normally, it takes me weeks of dedicated healthy stressless living (peat diet, yoga, sunshine etc.) to get this kind of mind.

Very eager to experiment more with this.

Excellent, thanks for the great feedback! Any info on dosing?
I get profound sense of relaxation when I take 10mg. No sleepiness, just calm and un-agitated state, even after a very stressful day.
 

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