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  1. Phungushead
    View attachment 53943 Research is first to demonstrate precisely how the compound lysergic acid diethylamide attaches to serotonin receptors in the brain

    “You can hear the Universal Symphony with God singing solo and Holy Ghost on drums,” was how Hunter S. Thompson described the experience, while the Beatles famously sang about “tangerine trees and marmalade skies”.

    Scientists are still some way from understanding how LSD brings about altered states of consciousness, but they have finally identified why acid trips last so long.

    A new study is the first to demonstrate precisely how the compound lysergic acid diethylamide (LSD) attaches to serotonin receptors in the brain.

    The images reveal that once the LSD compound latches on, part of the serotonin receptor folds down over it like a dustbin lid, meaning that it is held tightly in place allowing the drug to linger in the brain for up to 12 hours.

    Bryan Roth, a professor of pharmacology at University of North Carolina and a senior co-author on the study said: “It’s basically trapped in the receptor and can’t get out.”

    Roth’s interest in the subject was sparked after witnessing the effects of LSD on fellow music fans at Grateful Dead concerts in his youth.

    “It would be interesting to be in the parking lot hearing people wondering when their LSD experience was going to end,” says “A lot of people who take the drug are not aware of just how long it lasts.”

    However, it has taken two decades of painstaking trial and error to manage to transform the LSD and receptor into a crystallised form. This allowed the scientists to decipher its exact physical structure, using crystallography, a technique where x-rays are beamed into a material and the resultant diffraction pattern can be used to work out the exact spacing of the atoms.

    The study, published in Cell, also found that eventually brain cells respond to the attached molecule by sucking the receptor inwards, like a tortoise pulling its head into its shell, at which point the LSD is broken down.

    In future, the findings could help chemists produce shorter-acting versions of the drug that may be more suited to clinical use for anxiety or post traumatic stress disorder.


    Thursday 26 January 2017 12.33 EST

    Hannah Devlin Science correspondent
    The Guardian
    Images: Fredrik Skold/Alamy, Wacker et al
    https://www.theguardian.com/science...-so-long-lysergic-acid-diethylamide-serotonin
    ------------------------------------------------------------------

    Crystal Structure of an LSD-Bound Human Serotonin Receptor
    Daniel Wacker, Sheng Wang, John D. McCorvy, Robin M. Betz, A.J. Venkatakrishnan, Anat Levit, Katherine Lansu, Zachary L. Schools, Tao Che, David E. Nichol, Brian K. Shoichet, Ron O. , Bryan L. Roth

    Highlights

    • Crystal structure of the human 5-HT2B receptor bound to LSD is determined
    • LSD shows unexpected binding configuration in the orthosteric site
    • LSD has extremely slow on and off rate at 5-HT2B and 5-HT2A receptors
    • Accelerated LSD kinetics selectively reduce arrestin signaling at 5-HT2B and 5-HT2Az
    Summary

    The prototypical hallucinogen LSD acts via serotonin receptors, and here we describe the crystal structure of LSD in complex with the human serotonin receptor 5-HT2B. The complex reveals conformational rearrangements to accommodate LSD, providing a structural explanation for the conformational selectivity of LSD’s key diethylamide moiety. LSD dissociates exceptionally slow from both 5-HT2BR and 5-HT2AR—a major target for its psychoactivity. Molecular dynamics (MD) simulations suggest that LSD’s slow binding kinetics may be due to a “lid” formed by extracellular loop 2 (EL2) at the entrance to the binding pocket. A mutation predicted to increase the mobility of this lid greatly accelerates LSD’s binding kinetics and selectively dampens LSD-mediated β-arrestin2 recruitment. This study thus reveals an unexpected binding mode of LSD; illuminates key features of its kinetics, stereochemistry, and signaling; and provides a molecular explanation for LSD’s actions at human serotonin receptors.

    Full article here: http://www.cell.com/cell/fulltext/S0092-8674(16)31749-4

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Comments

  1. jalopez
    Thanks for the post! Weird thing is LSD's half life in the body is often approximated somewhere between 3 and 5 hours. This of course doesn't correlate well with how long the drug effects you or why the effects peak at the time they do. Makes me wonder what else is going on in the serotonin receptors.
  2. Budgetadvisoryservice
    I wonder if there's anything which could be done to slow down that effect, extending the duration of the trip.

    The comparison between a brain cell and a tortoise makes for a pretty trippy mental picture. It's a nice simile.
  3. Shampoo
    The half-life of a drug in the body is only a relevant matter with regards to the chemical, not it's effects. 5-HT receptors a g-coupled proteins, which means that once activated they induce a cascade of intracellular signals which are what actually impacts change in the cellular activity. If you look at the half-life of nearly any drug which acts through g-protein coupled receptors (CB1, 5-HT, Dopamine...etc.) you will see that the duration of activity is not directly correlated.

    As far as receptor-decoupling, there is not anything that can be done to slow down this effect. However, like with many other drugs there are two options for extending the duration - one is to slow/prevent the metabolic/enzymatic breakdown of the drug, in this case by inhibiting cytochrome P450 enzymes, and the other is to observe the mechanism by which the drug acts downstream, and enhance that, which in this case is activation of monamine receptors via release of DA/5-HT/NE. This can be achieved with a second drug which would prevent the breakdown of these released monoamines (i.e. a monoamine oxidase inhibitor or MAOI)
  4. Phungushead
    This is LSD attached to a brain cell serotonin receptor

    [IMGL="white"]https://drugs-forum.com/forum/attachment.php?attachmentid=53947&stc=1&d=1485536377[/IMGL] A tiny tab of acid on the tongue. A daylong trip through hallucinations and assorted other psychedelic experiences For the first time, researchers at the UNC School of Medicine have discovered precisely what the drug lysergic acid diethylamide (LSD) looks like in its active state when attached to a human serotonin receptor of a brain cell, and their first-ever crystal structure revealed a major clue for why the psychoactive effects of LSD last so long.

    Bryan L. Roth, MD, PhD, the Michael Hooker Distinguished Professor of Protein Therapeutics and Translational Proteomics in the UNC School of Medicine, led the research, which was published today in Cell.

    "There are different levels of understanding for how drugs like LSD work," Roth said. "The most fundamental level is to find out how the drug binds to a receptor on a cell. The only way to do that is to solve the structure. And to do that, you need x-ray crystallography, the gold standard."

    That is what Roth's lab accomplished—essentially "freezing" LSD attached to a receptor so his team could capture crystallography images. As it turns out, when LSD latches onto a brain cell's serotonin receptor, the LSD molecule is locked into place because part of the receptor folds over the drug molecule, like a lid. And then it stays put.

    "We think this lid is likely why the effects of LSD can last so long," said Roth, who holds a joint appointment at the UNC Eshelman School of Pharmacy. "LSD takes a long time to get onto the receptor, and then once it's on, it doesn't come off. And the reason is this lid."

    Eventually, though, an acid trip ends. Some LSD molecules pop off their receptors as the lid moves around. Also, brain cells eventually respond to this strange molecule by sucking the receptor into the cell, where it - along with the LSD—is degraded or disassembled for recycling.

    Postdoctoral researchers Daniel Wacker, PhD, and Sheng Wang, PhD, led the experiments to crystallize LSD bound to a serotonin receptor and discover why it stays bound so long. "Serotonin, obviously, hits this receptor on brain cells," Wacker said. "But our experiments show that serotonin does not interact with this lid in the same way LSD does."

    [IMGR="white"]https://drugs-forum.com/forum/attachment.php?attachmentid=53948&stc=1&d=1485536377[/IMGR] Although other labs have reported that LSD "washes" out of the brain's fluid within four hours, such experiments could not determine what was happening on or inside brain cells. Roth's lab has shown for the first time that LSD is very much not washed out of the serotonin receptors located within the membrane of brain cells in a few hours.

    How this popular drug causes such powerful effects has remained a mystery ever since Swiss scientist Albert Hofmann first accidently synthesized and dosed LSD to report its effects in 1938. Now, because of the work of Roth's lab, scientists can begin to parse how the drug sparks such a dramatic reaction in the brain, just as the scientific and medical communities renew interest in the drug as a potential treatment for a number of conditions, such as cluster headaches, substance abuse, and anxiety associated with life-threatening conditions.

    Solving the structure of LSD could help drug developers design better psychiatric drugs with fewer side effects. Also, although LSD is illegal, it remains a popular recreational drug and not just for its most potent effects. Some people - most notably technology developers in Silicon Valley and elsewhere - report "microdosing" LSD to boost creativity, relieve stress, and help them solve problems, while avoiding its hallucinogenic effects.

    One in 10 people in the United States—tens of millions of people—have reported using LSD at least once in their lives. "About 3 percent of all high school students—who are at an age when their brains are still developing—have reported trying it," Roth said. "And although the drug has been used for a long time, we don't know that much about it."

    [IMGL="white"]https://drugs-forum.com/forum/attachment.php?attachmentid=53949&stc=1&d=1485536377[/IMGL] Previous to becoming a pharmacology professor and researcher, Roth was a psychiatrist specializing in schizophrenia. Patients would occasionally report that their first schizophrenic break occurred while on LSD.

    "They were never the same again," Roth said. "Although this is rare, it has been reported. People also report flashbacks and LSD is an extremely potent drug. So for those reasons, along with its potential as part of therapeutic treatment, LSD is scientifically interesting."

    For two decades, Roth's lab—first at Case Western Research University and then upon his arrival at UNC in 2005 - had been trying to crystalize LSD attached to its receptor through a series of tedious and unsuccessful experiments. Others, too, have been trying. Without crystals, no one would be able to see what LSD bound to a receptor would look like.

    "To get crystals of a known compound bound to its receptor is incredibly difficult," said Roth, who is also director of the National Institute of Mental Health's Psychoactive Drug Screening Program housed at UNC. "In some cases, it's nearly impossible."

    For the past several years under Roth's guidance, the task fell to Wacker, who was the first scientist to determine the crystal structure of a serotonin receptor. That was nearly four years ago as a graduate student in the lab of Ray Stevens, PhD, formerly at the Scripps Institute.

    There are a few reasons why crystallizing LSD bound to a receptor is difficult. The first is lack of material; the receptors need to be produced in the lab using a number of tricks such as generating a virus that than infects cells and generates the receptor. Second, the receptors are incredibly flexible, even when compounds such as LSD are bound to them; the receptors do not want to sit still. Third, unlike, say, a molecule of water, a serotonin receptor is highly complex and composed of thousands of atoms.

    Wacker explained: "We need a lot of receptors to generate an image because of their small size - much smaller than the wavelength of visible light. Instead we use x-rays, but for that to work we need all of these receptors to sit perfectly still, and they all need to sit still in the same exact way, and that's what happens in crystals. So, even if you create a lot of serotonin receptors and attempt to crystallize them, one receptor might twitch in one direction, another receptor might twitch in another direction, a third receptor might not be bound to the LSD, and a fourth receptor might have a lid that moves a little more than the other receptors. So, we need to dissolve all these receptors in water and then slowly take away the water. The temperature needs to be just right. And then we need to employ all kinds of experimental tricks to continue to draw out the water and convince the molecules to sit still so that they will want to crystallize."

    It's sort of like letting soup sit out overnight, Wacker said. You'll notice salt crystals at the bottom. That's because the salt in the soup is dissolved in water, but then as water slowly evaporated over time, salt molecules latch onto each other to stay stable. The result: crystals.

    But serotonin receptors are not soup. Getting serotonin-LSD crystals took Wacker and colleagues two years, but once they got crystals, the serotonin receptors with LSD were packed tightly together. And that allowed them to shoot x-rays at the receptors, which allowed them to create images of atomic resolution.

    Then UNC postdoctoral researcher John McCorvy, PhD, discovered that the lid was the key to LSD being bound to its serotonin receptor. McCorvy and colleagues created mutant receptors with floppier lids, and they found that LSD bound more quickly and also detached from the receptor more easily. They also noticed that the shorter binding times led to different signaling patterns inside cells. These different patterns likely means that the effects of LSD would have been different than the typical effects with the lid tightly secured.

    Ron Dror, PhD, and his team at Stanford used computer simulations to confirm that this is what might happen when LSD engages its receptor protein in a human brain.

    [IMGR="white"]https://drugs-forum.com/forum/attachment.php?attachmentid=53950&stc=1&d=1485536377[/IMGR] "There is a headache drug that binds to the same receptor as LSD," Dror said. "The two drugs bind in the same receptor pocket, but the shape of that binding pocket is different when one drug or the other is bound. We used computer simulations to help explain why the two drugs favor different binding pocket shapes.

    Another aspect of this computational work focused on the fact that the receptor site is not static—the receptor and the drug are both highly dynamic. "They wiggle around all the time, Dror said. "It has long been observed that LSD trips are long. The simulations helped explain why the receptor holds onto LSD for so long despite the fact that they have such a dynamic connection."

    Roth said, "We do not advocate using LSD; it is potentially very dangerous. But it could have potential medicinal uses, some of which were reported in the medical literature decades ago. Now that we've solved the structure of LSD bound to a receptor, we are learning what makes it so potent."

    Wacker added, "I think it's important for the pharmaceutical industry to understand that if you modify just one tiny aspect of any compound, you might affect the way it sits in the receptor. And as a result, you might affect how the compound works.


    26 January 2017

    Phys.org

    Images:
    A molecule of LSD bound to a larger serotonin receptor. The 'lid' that keeps LSD bound so long is the orange bar running through the center. Credit: Lab of Bryan Roth, UNC School of Medicine
    Artistic representation of LSD (in blue) fitting into a serotonin receptor (the white ribbon). Credit: Bryan Roth
    Artistic representation of LSD -- highlighted in rainbow -- bound and trapped in the serotonin receptor (gray). Credit: Robin Betz, Stanford University
    Artistic representation of the chemical structure of LSD -- highlighted in yellow -- interlocking into a red-orange ribbon diagram of the serotonin receptor. Credit: Annie Spikes

    https://phys.org/news/2017-01-lsd-brain-cell-serotonin-receptor.html
  5. Calliope
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