N&PD Moderators: Skorpio
extraordinary pharmacology
dorothyperkins
Bluelighter
+ prism + something hot = IR spectrometer!
Actually it may be even cheaper!
http://www.metacafe.com/watch/395292/take_infrared_pictures_with_your_digital_camera/
Cool IR spec page btw, i never managed to find one that detailed.
Edit:
Who said u could?
Edit2:
lol
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Ham-milton
Bluelighter
Again, I'm no expert here, but I don't think it's remotely that simple. I mean, you could see take a look at what's being emitted, but without comparing the radiation pumped in to the emitted radiation, you're not really getting a full picture, right?
I'm not sure why the temperature of the body matters?
My wife says it doesn't either. Damn computer. I bet it can't transmit sarcasm very well, either.
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Acyl
Bluelighter
It isnt that simple, you've just read a wikipedia article and think you know everything about the theory.
I dont know everything about it either but my goal isnt to discredit it, if you really want to know how and why a bunch of graduate students and/or PhD's waste their time on something like this you should read
http://www.flexitral.com/research/chemical_senses_complete.pdf
I wouldnt come to any conclusions till all of it has been read.
dorothyperkins
Bluelighter
The background scan on a proper IR is a squiggly line that only varies from ~97-103%T i think. For a crude device it shouldnt make any difference.
Edit: Need to go to sleep but on the first page of the link: "The most striking instance is that of pure acetophenone and its fully
deuterated analogue acetophenone-d8, which smell different despite being identical in structure."
Surely thay cannot be described as identical in structure!
Ham-milton
Bluelighter
Acyl said:
I read all of this in 2005 or early 2006, plus the keller and vosshall paper shortly afterwards. I'm not sure what you mean by "a bunch" of PhDs, but there's been almost nothing published that confirms Turin's theory. Actually besides keller and vosshall, I can't think of anything that really looked at it critically.
But that's not exactly germane to the conversation here. Unless the topic has changed, I'm pretty sure we're discussing how the original poster's hypothesis could be applied to psychopharm, not Turin's.
As it was presented, the OP's hypothesis doesn't make sense. Would you prefer we discuss the application of Turin's hypothesis to psychopharm? There's a lot more there.
Oh, ouch, again your little ad hominem's and assumptions are just tearing me up inside.
Ham-milton
Bluelighter
dorothyperkins said:
LOL- where the hell did that come from??
Acyl
Bluelighter
Okay, I apologize for that. I tend to do that sometimes.
Well, I havent read much of that paper (just skimmed through a few paragraphs). What makes it not work?
I was under the impression that the characteristic IR stretches of certain molecules can be used to explain unique smells. I was under the impression that they were just relating IR to the interaction between compound/receptors instead of structure.
This relates to what the TS is talking about.
Ham-milton
Bluelighter
Well, they can, but the question, I suppose, comes down to whether the stretches have meaning beyond telling us what a molecule looks like. Turin puts forth the idea that there are 10 or more types of olfactory receptors, each type looking for the various stretches (10 doesn't seem like enough to me, he's done the math far more carefully than I have), and then the composite signal yields a specific scent in the brain.
The reason it "doesn't work" is just that it doesn't. On paper, he makes a convincing argument, but when it's tested in the lab very few to none of the things that'd be predicted from his hypothesis actually show up. For instance, using his theory, you'd expect to be able to blend compounds based upon their IR stretches to get a composite IR stretch matching another compound, and that when smelled together, the two compounds together would yield a scent the same as the compound that was matched. That didn't work in the lab.
We know so little about how we smell that a hypothesis like this can be put forth and we don't have enough research to confirm or deny it without doing a bunch of research.
When it comes to psychopharm, that's not the case, and actually, if you read under section 3 on page 4 (I'm pretty sure it's on page 4, but it might be just above section 3), he explains how a "biological spectroscope" system of receptors would need to exist in order to function. With all of the knowledge we have about receptor binding in the brain, we can rule out the existance of this sort of biological spectroscope existing in the brain.
If I understand it all correct, and that's no guarantee, for a Turin's Hypothesis to apply to psychopharm, there'd just be 10 types of receptors, and they'd all bind according to their stretches, not the way we know they do.
Things like cocaine, morphine, THC, LSD and whatever else would bind to common receptors, which we know doesn't happen.
Adrenochrome
Ex-Bluelighter
I feel this is (at best) unorthodox to the point of being quasipseudoscience
Ham-milton
Bluelighter
only quasipseudoscience? Damn, that's low.
Reminisant B
Greenlighter
quasipseudoscience is a googlewhack, haha
well I think technically a googlewhack needs two words:
quasipseudoscience quantitative
[EDIT] oh just realised it's a Googlewhackblatt [single word, single result]
Not for long though as this bluelight will no doubt come up as link soon.
http://en.wikipedia.org/wiki/Googlewhack
spectrasonic
Greenlighter
Well at least some dialogue has been stirred up.
But almost entirely about the mechanism and the physics needed to explain it.
For those with such concerns read Benveniste, Luca (several very detailed and deep pdfs at flexitral). I'm not too interested in the mechanism myself. Can't say I know what a tunnelling electron is.
Let me explain the way I see things:
Over the years, reading reports of compunds, their structures and effects, one thing has struck me (and just about everybody) repeatedly. And that is the mismatch between functional and structural categories. So it is said that a small change to a molecule may change its effects radically. That an amphetamine may have analgesic properties. That very different structures (opioid versus opiate I imagine) can produce similar effects.
The lock-and-key thing seems like a very poor analogy to me. If I put a slightly different key in my front door, it doesn't do anything. Whereas a whole bunch of structures may act at a receptor.
Now the incredible thing for me was reading Turin and seeing this exact same phenomenon in olfactory terms. So Turin checked out the compounds' spectroscopic nature and found that it better matched their activity. So he's put it to use, in a multi-billion dollar industry, and is busy producing odorant compounds. And this is the measure of any theory, that it has predictive power.
There's an article by Turin called "Rational Odorant Design"-This is what is sorely lacking in modern pharmacology, Rational Drug Design, although it was probably aspired to at one time. Pharmacologists merely tweak existing molecules and cross their fingers. Suppose you wished to invent a compound from scratch using the Standard Pharmacological Model. You want it to act at this receptor, and that receptor, and so on, as natural compounds frequently do. Can you take the various structures known to have these effects and glue them together to create a new molecule? Or look at the auditory effects of DIPT. These appear to have arisen by chance, but suppose we wish to design a compound which shares this effect. Which receptor do we need to involve. Are we waiting for a new receptor to be dicovered? Or is it a unique effect at an existing receptor. How about the different feel of different psychedelics, different geometries? How would such factors be controlled using the standard model of receptor interactions. Or do the molecules radiate different frequencies at the receptor?
And if anyone here feels an intense hostility for Turin and his ideas, there's really no need to add to this thread. I started it so as to transmit these ideas to receptive minds, who hopefully can take the ball and run with it.
Reminisant B
Greenlighter
^interesting things might come to light when the full power of quantum computing can be used to explore pattern matching between compounds and their variables.
I don't pretend to understand fully all the receptor / agonist theories etc however if there is a link between their frequencies, 3d structure, whatever quantum computing pattern matching might offer the best way to find the link. [simply due to the theoretical ability of comparing so many variables at once - something that the human mind would find to much of a struggle]
spectrasonic
Greenlighter
Ham-milton said:
I think I made it abundantly clear that Turin's model is what I'm offering. I don't offer it as my own. I only asked that it be extended to "psychopharm".
spectrasonic
Greenlighter
I found this. Looks like a good intro to Turin.
Olfaction (smell) is the most mysterious of senses, and is wrongly regarded as insignificant by most people. The sense of taste, for example, consists in large part of smell - try holding your nose next time you eat - and the recent identification of putative pheromone receptors in humans suggests that olfaction affects behaviour in as yet unknown ways.
The human nose, while not as sensitive as, say, that of a dog, can still detect very low concentrations of odorant molecules as they diffuse through the air. The initial event in the process of olfaction is the recognition of an odorant molecule by the olfactory receptors, which are proteins found in the olfactory epithelium. Olfactory receptors are transducers - they convert the ‘information’ in odorant molecules into electrical signals that are sent to the brain. It is only when these signals are processed in the olfactory cortex that we experience the smell.
While the higher order processing of the signals generated by olfactory receptors is relatively well understood, very little is known about how the receptors transduce the information contained in odorants into electrical signals. It has always been assumed that olfactory receptors function in the same way as other receptors - via the ‘lock and key’ mechanism. According to this well established model for the interaction of a receptor with its ligand (the molecule which binds to it), the receptor recognizes the three-dimensional shape of the ligand, and can only be activated by that specific molecule. Thus, in most cases, signal transduction begins with a molecular recognition event.
In the case of olfaction, however, there is a problem. A finite number of olfactory receptors recognize a seemingly infinite number of odorant molecules. So, although the shape and size of odorants is known to be important, olfactory receptors must also be detecting some other property of the odorants.
In the mid-1990s, Luca Turin, a biophysicist who was then at University College London, proposed a novel mechanism for olfactory receptor transduction. Few people, if any, know more about how the nose knows the difference between one odorant and another than Turin. He is, to borrow the title of a recent book about him, “the emperor of scent”. It is because of his expertise in olfaction that the French perfume houses consulted Turin about their new fragrances.
At UCL, Turin’s office doubled up as a makeshift laboratory. He spent much of his time in the long, narrow room, its walls lined from floor to ceiling with bottles of perfume, tirelessly investigating the relationship between the structures of thousands of aromatic compounds and their odours. His theory was published in the journal Chemical Senses:
…olfactory receptors respond not to the shape of the molecules but to their vibrations. [The theory provides] a detailed and plausible mechanism for biological transduction of molecular vibrations: inelastic electron tunnelling.
In a non-biological system, inelastic electron tunneling is “a non-optical form of vibrational spectroscopy [which] relies on the interaction between electrons tunneling across a narrow gap between metallic electrodes and a molecule in the gap”. In a biological system, such as the olfactory system, this would involve the tunneling of an electron between a suitable donor molecule and specific, electrically-charged amino acid residues within the olfactory receptor.
Turin’s theory was not controversial - he says it was “ignored rather than criticized”. But now, in a paper to be published in Physical Review Letters, Marshall Stoneham and colleagues, of UCL’s Department of Physics and Astronomy, report that they have performed calculations which suggest that Turin’s theory is feasible:
We test the viability of [Turin’s] mechanism using a simple but general model. Using values of key parameters in line with those of other biomolecular systems, we find the proposed mechanism is consistent both with the underlying physics and the observed features of smell, provided the receptor has certain qualities.
News of the paper has generated some interest in Turin’s theory of olfaction. But Turin, of course, has always been adamant that his theory is correct. Several years ago, he set up Flexitral, a company which designs odorant molecules for use by the perfume industry. At the company’s headquarters in Chantilly, Virgina, Turin and his colleagues have been using the theory to predict the smell of odorant molecules before synthesizing them. Turin’s theory explains not only how a limited number of olfactory receptors can detect a far larger number of odorants, but also why odorants with very similar molecular structures can smell very different, and, conversely, why molecules with different structures can have similar odours.
In order to gain some understanding of Turin’s theory, we first need to look at the structure of olfactory receptors. Olfactory receptors were first cloned by buck and Axel in 1991. In mammals, olfactory receptors are G-protein-coupled receptors (GPCRs). The GPCRs constitute the largest known protein superfamily. Mice have approximately 900 odorant receptor genes encoding 1,200 receptors, and humans have about 350 receptor genes.
GPCRs are embedded in the membrane of olfactory cells, and have a distinctive structural motif: the string of amino acids of which they are composed winds back and forth within the membrane, spanning it seven times.
GPCRs are named because they recruit intracellular proteins called G-proteins to transduce sensory signals. The exact mechanism of action of GPCRs is unknown, but very basically, it occurs as follows. When the receptor is inactive, it has an inactive G-protein bound to its intracellular surface. The binding of a ligand to the receptor’s extracellular surface causes a conformational change in the receptor, which results in the G-protein being activated. The activated G-protein is released from the olfactory receptor, and then binds to, and activates, other protein molecules within the cell, initiating a chain of biochemical reactions.
According to Turin’s theory, olfactory receptors act like biological spectroscopes, with the transduction of olfactory stimuli depending on the detection of activity on the subatomic scale. Turin proposes that the binding of an odorant mediates inelastic electron tunneling, whereby an electron is transferred from a donor molecule to the receptor. Tunneling of electrons across the odorant’s binding site activates the receptor and causes the odorant to vibrate. It is these patterns of vibrations which are specific to the odorant, and which are detected by the olfactory receptors. Even the slightest difference in molecular structure therefore produces a different vibrational spectrogram. Together, the series of receptors in the olfactory epithelium cover the vibrational spectrum, and therefore can detect all possible odorants.
So what evidence is there that electron tunnelling takes place in olfactory receptors? As mentioned earlier, Turin is successfully using his theory to predict the odor of chemicals before they are synthesized. Turin’s also theory makes a number of predictions about the functional properties of olfactory receptors. Firstly, because most odorants cannot undergo reduction-oxidation (or electron exchanging) reactions, the receptors must obtain the electrons used for tunnelling from another source, perhaps a soluble electron carrier or an enzyme. And, because many enzymes which transfer electrons require binding of metal ions, olfactory receptors may also be expected to have metal binding sites.
Analysis of DNA sequences of olfactory receptors shows that these predictions are correct. The olfactory receptors which have been sequenced are now known to contain a binding site for a molecule called nicotanamide adenine dinucleotide phosphate (NAD(P)H), a cofactor molecule which binds to enzymes and exchanges electrons with them. Sequence analysis also shows that olfactory receptors have sequences that are closely related to, and that function as, zinc binding sites. Zinc is known to be involved in olfacation, as a deficiency of the metal results in temporary, reversible anosmia (the inability to smell), but its exact role is unclear. Turin suggests that the zinc binding sites in the olfactory receptors are involved in binding G-proteins, and that the zinc ions themselves contribute to a molecular ‘bridge’ through which electrons tunnel during the transduction process.
spectrasonic
Greenlighter
This is interesting in that its from earlier this year:
http://www.physorg.com/news89542035.html
Adrenochrome
Ex-Bluelighter
spectrasonic: Nice thread, and i still haven't read anything you said, so pardon me if I'm being an ass, but you do realize:
i.e., No more key-lock theory, we now use the induced fit theory...
Refluxer said:
LuxEtVeritas
Bluelighter
This appears plausible and that it distinctly works for olfaction...having brdiged interactions is nothing tha hard to fathom at a basic level
some receptors like olfaction which work with thousands of "agonists transducers" would likely require a different compensatory system
Ham-milton
Bluelighter
Alright, this is just getting retarded. You're not interested in the mechanism, but you cling to the idea that there's a biological spectroscope that's responsible for the responses that psychoactive drugs produce?
If you're going to say, "lets take Turin's theory and apply it to psychopharmacology" (which you didn't say- you claimed you just found it 2 days ago, and gave us your own ideas about it), then let's do that.
Here's the reasons why Turin's hypothesis (sorry for using 'theory') can't apply to psychopharm-
1. We know what receptors ligands bind to.
2. We know what receptors exist (though there are probably a few we haven't)
We know that the set of receptors Turin predicted don't exist. If they did, we'd have a completely different set of receptors in our brain.
You keep saying tons and tons about nothing. It's like "80 ways I can link olfactory receptors to brain receptors"- big fucking deal. They're both g-proteins. Big deal, guy.
I know lots about Turin's hypothesis, and about how it's been disproven. I know a few morons cling to it, but c'mon- there's a few tiny little things that give it a little credence, but they're better explained by other hypotheses.
I just don't understand why anyone would cling to the idea for olfactory receptors. They're probably the least understood receptors, though, so I suppose you can push this theory on them just because we don't know enough yet to say "nope, that's just not how it is."
But to attempt to apply it to CNS receptors??? No, there's just no way. I mean, you obviously did a lot of research- but you did it on the wrong things. Go read through all 35 pages in the flexitral page Acyl linked to earlier. If you can read that and still say that you think this is a plausible explanation... Well, if you can do that... maybe you should lay off the crack pipe :/
And by the way, barring a few exceptions, opiates and opioids don't really have that varied of structures. They all follow the same morphine rule, though they may break a part of it, they'll fit with the rest.
spectrasonic
Greenlighter
Dr Andrew Horsfield, of the London Centre for Nanotechnology, the UCL Department of Physics & Astronomy and one of the senior authors of the study, says: “Vibration theory has been around for a while but has lacked the answer to a crucial question: how could a biological system make the kind of measurements of vibrations which normally require a piece of lab kit like a spectroscope. This mechanism is more like swipe-card identification than a key fitting a lock.
“Back in 1996, a UCL researcher, Dr Luca Turin* revived the theory by suggesting that smell receptors acted like switches tuned to different frequencies across the vibration spectrum. When an odorant molecule with the correct vibration binds to the receptor it closes the switch and allows the electrons to flow. This signal is amplified and sent to the brain. Each molecule has a distinctive vibration pattern and therefore a unique smell. However, Turin’s proposal lacked mathematical rigour and the physical mechanism to back it up.”
In the latest UCL paper, the researchers propose a viable physical mechanism that fits with both the laws of physics and observed features of smell.
Professor Marshall Stoneham, of the London Centre for Nanotechnology, the UCL Department of Physics & Astronomy and one of the senior authors of the study, added: “The key to determining whether the vibration model works lies in the rate that electrons move around either in the presence or absence of an odour. Our calculations show that electron flow increases significantly in the presence of an odour, suggesting there’s mileage in vibration theory.
“Furthermore, this type of receptor activation, which essentially relies on ‘biological electronics’, was previously unknown and could explain how other systems in the body operate.”
Dr. Horsfield and Prof. Stoneham were however disappointed by the reaction of precocious pharmapunk genius Mr Ham Milton who was quoted as saying "I know lots about Turin's hypothesis, and about how it's been disproven. I know a few morons cling to it, but c'mon...."