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Diphenoxylate - a non-analgesic opiate

wouldn't it eventually get into the system? I just don't understand why if it crosses the BBB (poorly though) through other routes why wouldn't that work, even if it is dangerous and a really bad idea. is it that it has to go through metabolism first? isn't it dissolved in the liquid solutions?
 
If FnB is correct on the insolubility (and/or if there weren't any more soluble salts available), then the liquid preparations would be suspensions (or colloids), not solutions, and therefore would have trouble passing through the BBB.
 
fastandbulbous said:
Diffusion - doesn't happen if not in solution (unless you have big holes in your BBB! =D)
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Oh I think I misunderstood what you were saying. You mean to say that a drug must be soluble in blood, correct?

Even so, what about active transport? Certainly there are things which cannot cross BBB via diffusion, but are actively transported in and out.-DG
 
Shit, I didn't notice the second page. Please, delete this post.
 
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I know this thread is super old but....
Actually I think very water soluble things are less likely to cross the BBB. We know that lipophilic molecules are more likely to pass through, as they readily diffuse through membranes. Being more soluble in water makes it easier to exclude from the BBB. This is why you can just eat plain neurotransmitters and get them in the brain. There arer other mechanisms to transport low solubility drugs around the body, either bound in albumin or in LDLs. the bioavailability might be quite low but the ability for this to penetrate the BBB might be even better because of it's low solubility. It's not super easy to predict, all I'm saying is that water solubility is a poor predictor of this. Check out Lipinski's Rule of Five for some info on drug like ness and hydrophobicity, although this doesn't deal with the BBB. http://en.wikipedia.org/wiki/Lipinski's_Rule_of_Five
I know only the idea of what the octanol partitioning coefficient is, but I think that might be a better predictor of crossing the BBB. A not to hot not to cold type thing.
I wonder if a nasal route would work well with this...
 
it could be that these findings are BS. I know people in pharma ind.. If u think for second that alotta shady shit dont go down like it does in anyother big ind. like banking/oil/cigarettes etc... think again. I would not b surprised if these results wer bias or even that the study wasn't performed right :/
 
^Yes - that is perfectly possible.

The patent on the replacement for diphenoxylate (loperamide) is interesting. They give ratios between the dose required to reduce gut motility & the dose required to produce analgesia. They chose the one with the biggest ratio... 615! If nothing else, it does give an insight into the QSAR for this class of compound. That -Cl really makes a difference to central activity!
 
BTW I noted that due to it's insolubility in water, when they injected rats & the like with diphenoxylate, it was a propylene glycol solution.
 
(zonk) said:
it could be that these findings are BS. I know people in pharma ind.. If u think for second that alotta shady shit dont go down like it does in anyother big ind. like banking/oil/cigarettes etc... think again. I would not b surprised if these results wer bias or even that the study wasn't performed right :/
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Like all the hoo-ha over whether SSRIs are addictive. Calling it a 'discontinuation syndrome' is just an attempt to give withdrawl symptoms some media friendly name...
 
fastandbulbous said:
Does anybody have any information or ideas as to why diphenoxylate has all of the characteristics of other opiates (abuse potential, substitutes for others in preventing withdrawl, reduces gastric motility, depresses breathing etc) but shows no properties as an analgesic. I was under the impression that if a drug was a mu receptor agonist, then it would also have analgesic properties.

Any insights would be appreciated
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Are there any lawsuits against the administration of ORLAMM?
 
I see this is a very old thread but it caught my interest. How did they classify this compound as an opioid, by receptor screening or by naloxone challenge? If the second then it doesn't have to be an opioid. Naloxone also causes nasty symptoms with dissociatives for example, I reacted horribly (no physical w/d but mental symtoms like agony, loneliness and tears) to it when I had no opioid tolerance at all and just memantine in my system.
 
plumbus-nine said:
I see this is a very old thread but it caught my interest. How did they classify this compound as an opioid, by receptor screening or by naloxone challenge? If the second then it doesn't have to be an opioid. Naloxone also causes nasty symptoms with dissociatives for example, I reacted horribly (no physical w/d but mental symtoms like agony, loneliness and tears) to it when I had no opioid tolerance at all and just memantine in my system.
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That could’ve also been due to it blocking your normal endo opioids, hard to say in that case..

I agree with your naloxone statement, naloxone blocks the effects of non-opioid drugs too at times.

-GC
 
G_Chem said:
That could’ve also been due to it blocking your normal endo opioids, hard to say in that case..
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Yeah, thought about that but naltrexone is routinously given to alcoholics with seemingly little side effects in comparison. Both are antagonists which turn into inverse agonists when tolerance is present. Would think it'd hit the alchoholics similarly like it did me but this doesn't seem to be much of an issue. I had a low, single digit figure of naloxone (from part of a tilidin/naltrexone pill I crushed and snorted, believing the naloxone would only work when injected) and the effects were, while short lived, heavy and hard to bear. Possibly does memantine in higher dosages than usually used (I had 40mg/d if I remember correctly) release endorphines? Idk.
 
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It may be a rare example of a MOR ligand with no NOP affinity? It's LogP is awfully close to violating Lipinski's Rules of 5. I've mused if altering the carboxylic acid moiety to carboxamide would help - an extra hydrogen bond acceptor. Makes it closer to piritramide (which most certainly is a strong opioid).

If it worked, it would almost certainly be a target for RC vendors. Only 1 company in India still produces difenoxin, but it isn't controlled in many places and it's hardy a difficult synthesis. In fact, it's possibly the EASIEST. 1)Form ammonium salt 2)dehydrate.
 
plumbus-nine said:
Yeah, thought about that but naltrexone is routinously given to alcoholics with seemingly little side effects in comparison. Both are antagonists which turn into inverse agonists when tolerance is present. Would think it'd hit the alchoholics similarly like it did me but this doesn't seem to be much of an issue. I had a low, single digit figure of naloxone (from part of a tilidin/naltrexone pill I crushed and snorted, believing the naloxone would only work when injected) and the effects were, while short lived, heavy and hard to bear. Possibly does memantine in higher dosages than usually used (I had 40mg/d if I remember correctly) release endorphines? Idk.
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Alcoholism has deep ties with the opioid system so I’m not sure that’s a good comparison either. Mu knockout mice not only stop self administering ethanol, they actually become averse to it.

-GC
 
Well I did research an alcohol alternative... and it's a benzodiazepine. I would say that the positive effects of ethanol are almost all GABA mediated but what I would consider negative effects (ataxia, loss of executive control, aggression, retrograde amnesia and hypnosis) are mediated by some other pathway.

Alcohol releases endorphins. I think it does so because ethanol is a toxin, acetaldehyde much more so. So maybe the body feels pain due to the acetaldehyde and that's the physiological response.

BUT I have to admit, what we actually got was a 'drunk pill' because up to 15mg it does nothing, at 20mg you are pretty wasted and at 30mg you are awake, but glued to the seat (in a good way). People who have also sampled methaqualone said the alcohol mimic was very similar...
 
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