Hallucinogenic Opiates?

[jaguraguguru]

Buprenorphine is considerably larger than any opioid that i can think of offhand and certainly larger than any of the traditional ones like morphine, heroin, fentanyl, methadone, etc in terms of both physical size and molecular weight.

These all fit the same receptor pocket, so they're all going to be roughly the same size.

That's absolutely ridiculous to assume that because they bind to the same receptor, that they are roughly the same size. Small molecules bind to the same receptors that much, much larger peptides bind to and they are certainly not even similar in size or scope. Also, they obviously don't bind in the same way and possibly not even in the same pocket. Buprenorphine is a powerful antagonist and probably has (at least) two binding modes, one agonistic and one antagonistic. It's incredibly simplistic to assume that because two different molecules bind to the same receptor that they bind in the same place, in the same way, or are of the same size or chemistry.

I don't really understand why you're so opposed to the suggestion that it may be a slight NMDA antagonist, and by slight I don't mean at the mM range, but in the low micromolar or high nanomolar. Have you tested it for NMDA antagonism? I'm sure not. You're only saying that because you haven't seen anything demonstrating it to be (nor have you found anything to the opposite I'm sure). I have done research on the subject and I found nothing even alluding to buprenorphine having been tried on NMDAR. I did come out at first and make the claim that it is an NMDA antagonist, but have since rescinded that straight-out claim and instead made a conjecture based on subjective effects and chemical information. I can't see why this conjecture would be "nonsensical," it's just not what you think.

Anyway, I wasn't trying to make this into an argument, just trying to discuss the subject, and for some reason you feel the necessity to offend me at each point. I used the wrong wording earlier. I was only making a suggestion, there is no need to offend me because of it.

 

[vicodelicious]

The only semi-hallucinogenic opiate I have experienced was some brand of butorphanol. I believe it was in the form of Stadol. Due to its partial agonist and antagonist activity at the μ-opioid receptor, and more importantly its affinity at the k-opioid center, I did get some rather interesting visual and hallucinogenic affects from the dose. I wouldn't say it was anything like a full LSD or psilocybin intensity, but DEFINITELY some rather interesting visual aspects to it.

A can't think o any more opioid/partial opioid agonists that have any affinity at the k-opioid center...

Oh and another tidbit from wikipedia:

It has long been understood that kappa-opioid receptor agonists are dysphoric[7] but dysphoria from kappa opioids has been shown to differ between sexes[8][9] More recent studies have shown the aversive properties in a variety of ways[10] and the kappa receptor has been strongly implicated as an integral neurochemical component of addiction and the remission thereof.

It is now widely accepted that κ-opioid receptor (partial) agonists have hallucinogenic ("psychotomimetic") effects, as exemplified by salvinorin A. These effects are generally undesirable in medicinal drugs and could have had frightening or disturbing effects in the tested humans. It is thought that the hallucinogenic effects of drugs such as butorphanol,nalbuphine, and pentazocine serve to limit their opiate abuse potential. In the case of salvinorin A, a structurally novel neoclerodane diterpene κ-opioid receptor agonist, these hallucinogenic effects are sought after. While salvinorin A is considered a hallucinogen, its effects are qualitatively different than those produced by the classical psychedelic hallucinogens such as LSD or mescaline.[11]

Thats all I got right now. Too much Xanax and buprenorphine tonight...

 

[pyrrho]

Salvinorin A and B are technically hallucinogenic opoids...

 

[Hammilton]

That's absolutely ridiculous to assume that because they bind to the same receptor, that they are roughly the same size. Small molecules bind to the same receptors that much, much larger peptides bind to and they are certainly not even similar in size or scope. Also, they obviously don't bind in the same way and possibly not even in the same pocket. Buprenorphine is a powerful antagonist and probably has (at least) two binding modes, one agonistic and one antagonistic. It's incredibly simplistic to assume that because two different molecules bind to the same receptor that they bind in the same place, in the same way, or are of the same size or chemistry.

Buprenorphine is larger than any other opiate you're aware of? Um.. no. It's not all that different than morphine. Only marginally larger. It depends how you feel like measuring, I suppose. I enjoyed the "That's absolutely ridiculous..." part. In order for a molecule to bind to the same receptor and produce the same effect, they need to have roughly the same size, shape, etc. This is practically the whole basis for SAR studies. There's a good understanding of the pharmacophore of various classes of substances. Consider benzodiazepines. As Morphiquet discussed at blacklight recently, between benzodiazepines, zolpidem, zopiclone, the beta-carbolines, etc etc have similar features in similar places, despite radically different structures. This is because to produce an agonist effect, a drug has to bind to one protein in the right spot and stabilize a conformation that will produce the right effects. It's also why the morphine rule is so well established. It's hard to find any opioid that doesn't conform to at least a few points of it.

I don't actually know if this is even true. Most of the small molecule agonists I'm aware of bind to receptors with fairly small endogenous ligands (for instance, met-enkephalin is only four AA's long). There may be much smaller ligands that are capable of binding to the same receptor, but I'm not really aware of any off the top of my head. However, even if there are proteins or peptides that bind to the same receptors that much smaller agonist molecules bind to, that doesn't mean much here. Due to the chain-like nature of peptides, it's quite possible that the entire peptide doesn't bind. Admittedly, this is really not an area I'm familiar with at all. PsychedelicPeptide will have a much more informed opinion on this.

So you're suggesting that there is an undiscovered allosteric site that binds ligands of opposite stereochemistry of ligands that already bind? If this were the case, then you would expect all of these dextro phenanthrene opioids to have relevant affinity. This isn't simplistic, it's just grasping at straws.

I can't see why this conjecture would be "nonsensical," it's just not what you think.

Because it isn't based in sense. You're even suggesting a novel allosteric site. hah!

I have done research on the subject and I found nothing even alluding to buprenorphine having been tried on NMDAR.

You couldn't possibly have done so, because I found it within five minutes.

Buprenorphine is a powerful antagonist and probably has (at least) two binding modes, one agonistic and one antagonistic. It's incredibly simplistic to assume that because two different molecules bind to the same receptor that they bind in the same place, in the same way, or are of the same size or chemistry.

You don't even seem to understand the basics of this, which makes this pretty funny. Buprenorphine is a partial agonist at mu receptors, and full antagonist at kappa. You don't even seem to understand what a partial agonist is. It doesn't bind in two different modes producing agonist and antagonist effects. That's not how it works. You should do some reading on the subject, even just Wikipedia, because this is very basic.

Buprenorphine binds the same way, but it has less efficacy, so it produces weaker agonist effects. Read about how this works. it doesn't have to bind in a different manner to do so. This doesn't have anything to do with NMDA antagonism, but this does give away your lack of knowledge on the subject.

It's incredibly simplistic to...

No, again, it's really not at all. It's just how things work. The lock and key analogy here is a good one, actually. They need to be about the same. To unlock your door, you need a key that conforms to pretty specialized shapes. An exact key will open it easily, this could be thought of an agonist. You might be able to open it with a similar key if you take your time, with a little wiggling. This would be the partial agonist. A key that would fit in the lock, but couldn't even turn it would be the antagonist.

Oh well I'm getting tired and I need to take a short nap now.