USA - Psychoactive compound activates mysterious receptor

[chillinwill]

A hallucinogenic compound found in a plant indigenous to South America and used in shamanic rituals regulates a mysterious protein that is abundant throughout the body, University of Wisconsin-Madison researchers have discovered.

The finding, reported in the Feb. 13 issue of Science, may ultimately have implications for treating drug abuse and/or depression. Many more experiments will be needed, the researchers say.

Scientists have been searching for years for naturally occurring compounds that trigger activity in the protein, the sigma-1 receptor. In addition, a unique receptor for the hallucinogen, called dimethyltryptamine (DMT), has never been identified.

The UW-Madison researchers made the unusual pairing by doing their initial work the "old-fashioned," yet still effective, way. They diagrammed the chemical structure of several drugs that bind to the sigma-1 receptor, reduced them to their simplest forms and then searched for possible natural molecules with the same features. Biochemical, physiological and behavioral experiments proved that DMT does, in fact, activate the sigma-1 receptor.

"We have no idea at present if or how the sigma-1 receptor may be connected to hallucinogenic activity," says senior author Arnold Ruoho, chair of pharmacology at the UW-Madison School of Medicine and Public Health. "But we believe that the National Institute on Drug Abuse (NIDA) may be interested in biological mechanisms underlying psychoactive and addictive drug action."

In addition to being a component of psychoactive snuffs and sacramental teas used in native religious practices in Latin America, DMT is known to be present in some mammalian tissues, and it has also been identified in mammalian blood and spinal fluid. Elevated levels of DMT and a related molecule have been found in the urine of schizophrenics.

Ruoho speculates that the hallucinogen's involvement may mean that the sigma-1 receptor is connected in some fashion to psychoactive behavior. When his team injected DMT into mice known to have the receptor, the animals became hyperactive; mice in which the receptor had been genetically removed did not.

"Hyperactive behavior is often associated with drug use or psychiatric problems," says Ruoho. "It's possible that new, highly selective drugs could be developed to inhibit the receptor and prevent this behavior."

The study revealed an additional neurologic link by confirming that the sigma-1 receptor and some compounds that bind to it inhibit ion channels, which are important for nerve activity. Work by many researchers — including some from UW-Madison — initially showed this relationship in earlier studies.

Some studies have also linked the receptor to the action of antidepressant drugs, and National Institutes of Health (NIH) scientists recently found that it appears to serve as a "chaperon," helping proteins to fold properly.

The Wisconsin researchers found that DMT is derived from the naturally occurring amino acid tryptophan and is structurally related to the neurotransmitter serotonin. This finding, Ruoho says, illustrates the mantra often used in the biological processing of natural molecules: Nothing goes to waste.

"Our findings support the idea that biochemical alterations of molecules such as tryptophan can produce simple compounds such as DMT that may target other regulatory pathways served by sigma-1 receptors," he says.

DMT may also reflect the presence of an even larger family of natural compounds that arise from other structurally related amino acids that may further regulate the receptor, Ruoho adds.

"It may well be that these different, naturally derived chemical forms regulate the sigma-1 receptor in tissue and organ-specific ways," he says.

by Dian Land
February 12, 2009
University of Wisconsin-Madison News
http://www.news.wisc.edu/16282

[Jasim]

WTF. There's some funny lines in this article.

"But we believe that the National Institute on Drug Abuse (NIDA) may be interested in biological mechanisms underlying psychoactive and addictive drug action."

Duh.

The Wisconsin researchers found that DMT is derived from the naturally occurring amino acid tryptophan and is structurally related to the neurotransmitter serotonin.

Really? They found that DMT is derived from tryptophan? And that it is structurally related to serotonin?
Like no one knew this before?!
Geez, in that case I should have published something then, since it is kinda obvious.


On a serious note, if DMT binds to sigma-1 then it could be a very valuable research tool. I'm guessing that funding may soon become available for DMT research.


I didn't know much at all about the sigma-1 receptor. So I did a little research and thought I would share since it's not a commonly discussed one.

The sigma-1 receptor is a transmembrane protein (possibly linked to G-proteins) found primarily in the CNS. It was originally classified as an opiate receptor, but this classification was reconsidered and dropped after failed attempts to block agonist activity with naloxone and naltrexone (which characteristically block opiate receptors). Interestingly the sigma-1 receptor has little homogeneity with any other known mammalian proteins. This is in dramatic contrast to other neuronal receptors which typically have a lot of genetic similarities.

Other than DMT, the sigma-1 receptor also has lower affinities for haloperidol, cocaine and certain neurosteroids.

In addition, the sigma-1 receptor modulates release of calcium ions and inhibits voltage-gated potassium channels via unknown mechanisms.

There are other sigma receptors, which I didn't find much on. I'm interested in learning more about this family of receptors.

Thanks for the article chillinwillin!

Reputation Comments on this post:

informative post

[Ilsa]

Originally Posted by Jasim

WTF. There's some funny lines in this article.

Duh.

Really? They found that DMT is derived from tryptophan? And that it is structurally related to serotonin?
Like no one knew this before?!
Geez, in that case I should have published something then, since it is kinda obvious.


On a serious note, if DMT binds to sigma-1 then it could be a very valuable research tool. I'm guessing that funding may soon become available for DMT research.


I didn't know much at all about the sigma-1 receptor. So I did a little research and thought I would share since it's not a commonly discussed one.

The sigma-1 receptor is a transmembrane protein (possibly linked to G-proteins) found primarily in the CNS. It was originally classified as an opiate receptor, but this classification was reconsidered and dropped after failed attempts to block agonist activity with naloxone and naltrexone (which characteristically block opiate receptors). Interestingly the sigma-1 receptor has little homogeneity with any other known mammalian proteins. This is in dramatic contrast to other neuronal receptors which typically have a lot of genetic similarities.

Other than DMT, the sigma-1 receptor also has lower affinities for haloperidol, cocaine and certain neurosteroids.

In addition, the sigma-1 receptor modulates release of calcium ions and inhibits voltage-gated potassium channels via unknown mechanisms.

There are other sigma receptors, which I didn't find much on. I'm interested in learning more about this family of receptors.

Thanks for the article chillinwillin!

yeah, the bit about NIDA interest was definitely amusing

re: sigma-1 inhibition of voltage-gated K+ channels is intriguing...transmembrane proteins that mediate ion channel regulatory mechanisms sounds a lot like a GPCR....curiouser and curiouser.....

[lineartransform]

Some very interesting research on DMT coming out of the University of Wisconsin. Short version - DMT has been found to activate the sigma-1 receptor which is linked to "the action of antidepressant drugs, and National Institutes of Health (NIH) scientists recently found that it appears to serve as a "chaperon," helping proteins to fold properly."

http://www.news.wisc.edu/16282

Psychoactive compound activates mysterious receptor
Feb. 12, 2009
by Dian Land

A hallucinogenic compound found in a plant indigenous to South America and used in shamanic rituals regulates a mysterious protein that is abundant throughout the body, University of Wisconsin-Madison researchers have discovered.

The finding, reported in the Feb. 13 issue of Science, may ultimately have implications for treating drug abuse and/or depression. Many more experiments will be needed, the researchers say.

Scientists have been searching for years for naturally occurring compounds that trigger activity in the protein, the sigma-1 receptor. In addition, a unique receptor for the hallucinogen, called dimethyltryptamine (DMT), has never been identified.

The UW-Madison researchers made the unusual pairing by doing their initial work the "old-fashioned," yet still effective, way. They diagrammed the chemical structure of several drugs that bind to the sigma-1 receptor, reduced them to their simplest forms and then searched for possible natural molecules with the same features. Biochemical, physiological and behavioral experiments proved that DMT does, in fact, activate the sigma-1 receptor.
"We have no idea at present if or how the sigma-1 receptor may be connected to hallucinogenic activity," says senior author Arnold Ruoho, chair of pharmacology at the UW-Madison School of Medicine and Public Health. "But we believe that the National Institute on Drug Abuse (NIDA) may be interested in biological mechanisms underlying psychoactive and addictive drug action."

In addition to being a component of psychoactive snuffs and sacramental teas used in native religious practices in Latin America, DMT is known to be present in some mammalian tissues, and it has also been identified in mammalian blood and spinal fluid. Elevated levels of DMT and a related molecule have been found in the urine of schizophrenics.

Ruoho speculates that the hallucinogen's involvement may mean that the sigma-1 receptor is connected in some fashion to psychoactive behavior. When his team injected DMT into mice known to have the receptor, the animals became hyperactive; mice in which the receptor had been genetically removed did not.

"Hyperactive behavior is often associated with drug use or psychiatric problems," says Ruoho. "It's possible that new, highly selective drugs could be developed to inhibit the receptor and prevent this behavior."
The study revealed an additional neurologic link by confirming that the sigma-1 receptor and some compounds that bind to it inhibit ion channels, which are important for nerve activity. Work by many researchers — including some from UW-Madison — initially showed this relationship in earlier studies.

Some studies have also linked the receptor to the action of antidepressant drugs, and National Institutes of Health (NIH) scientists recently found that it appears to serve as a "chaperon," helping proteins to fold properly.
The Wisconsin researchers found that DMT is derived from the naturally occurring amino acid tryptophan and is structurally related to the neurotransmitter serotonin. This finding, Ruoho says, illustrates the mantra often used in the biological processing of natural molecules: Nothing goes to waste.

"Our findings support the idea that biochemical alterations of molecules such as tryptophan can produce simple compounds such as DMT that may target other regulatory pathways served by sigma-1 receptors," he says.
DMT may also reflect the presence of an even larger family of natural compounds that arise from other structurally related amino acids that may further regulate the receptor, Ruoho adds.

"It may well be that these different, naturally derived chemical forms regulate the sigma-1 receptor in tissue and organ-specific ways," he says.

[dutch-marshal]

Receptor's Binding Partner Identified
Shamans' hallucinogen that is also produced by the body binds to nervous system receptor

by Sophie L. Rovner

A hallucinogenic compound found in psychoactive snuffs and sacramental teas used in native shamanic rituals in South America has helped elucidate the role of a receptor found throughout the nervous system. The sigma-1 receptor was known to bind many synthetic compounds, and it was originally mischaracterized as a receptor for opioid drugs. But its real role in the body remains unknown. However, Arnold E. Ruoho of the University of Wisconsin, Madison, and colleagues have now solved one part of the mystery: They have discovered that the receptor's endogenous ligand is N,N-dimethyltryptamine (DMT) (Science 2009, 323, 934).

DMT is not only found in hallucinogenic teas and snuffs but is also produced by enzymes in the body. It's been detected in human urine, blood, and cerebrospinal fluid; in the mammalian lung; and in rodent brains. At least in rodents, DMT levels rise in stressful conditions. Ruoho's group found that DMT inhibits voltage-gated sodium ion channel activity when it binds to sigma-1 receptors on cells.

Chemical & Engineering News

Reputation Comments on this post:

I find this thread very interesting, dmt has a usefulness to the medical community

[beentheredonethatagain]

http://www.sciencedaily.com/releases/2009/...

The finding, reported in the Feb. 13 issue of Science, may ultimately have implications for treating drug abuse and/or depression. Many more experiments will be needed, the researchers say.

Scientists have been searching for years for naturally occurring compounds that trigger activity in the protein, the sigma-1 receptor. In addition, a unique receptor for the hallucinogen, called dimethyltryptamine (DMT), has never been identified.

The UW-Madison researchers made the unusual pairing by doing their initial work the "old-fashioned," yet still effective, way. They diagrammed the chemical structure of several drugs that bind to the sigma-1 receptor, reduced them to their simplest forms and then searched for possible natural molecules with the same features. Biochemical, physiological and behavioral experiments proved that DMT does, in fact, activate the sigma-1 receptor.

"We have no idea at present if or how the sigma-1 receptor may be connected to hallucinogenic activity," says senior author Arnold Ruoho, chair of pharmacology at the UW-Madison School of Medicine and Public Health. "But we believe that the National Institute on Drug Abuse (NIDA) may be interested in biological mechanisms underlying psychoactive and addictive drug action."

In addition to being a component of psychoactive snuffs and sacramental teas used in native religious practices in Latin America, DMT is known to be present in some mammalian tissues, and it has also been identified in mammalian blood and spinal fluid. Elevated levels of DMT and a related molecule have been found in the urine of schizophrenics.

Ruoho speculates that the hallucinogen's involvement may mean that the sigma-1 receptor is connected in some fashion to psychoactive behavior. When his team injected DMT into mice known to have the receptor, the animals became hyperactive; mice in which the receptor had been genetically removed did not.

"Hyperactive behavior is often associated with drug use or psychiatric problems," says Ruoho. "It's possible that new, highly selective drugs could be developed to inhibit the receptor and prevent this behavior."

The study revealed an additional neurologic link by confirming that the sigma-1 receptor and some compounds that bind to it inhibit ion channels, which are important for nerve activity. Work by many researchers - including some from UW-Madison - initially showed this relationship in earlier studies.

Some studies have also linked the receptor to the action of antidepressant drugs, and National Institutes of Health (NIH) scientists recently found that it appears to serve as a "chaperon," helping proteins to fold properly.

The Wisconsin researchers found that DMT is derived from the naturally occurring amino acid tryptophan and is structurally related to the neurotransmitter serotonin. This finding, Ruoho says, illustrates the mantra often used in the biological processing of natural molecules: Nothing goes to waste.

"Our findings support the idea that biochemical alterations of molecules such as tryptophan can produce simple compounds such as DMT that may target other regulatory pathways served by sigma-1 receptors," he says.

DMT may also reflect the presence of an even larger family of natural compounds that arise from other structurally related amino acids that may further regulate the receptor, Ruoho adds.

"It may well be that these different, naturally derived chemical forms regulate the sigma-1 receptor in tissue and organ-specific ways," he says.

Adapted from materials provided by University of Wisconsin-Madison.

[chillinwill]

Entheogen and hallucinogen, N,N'-dimethyltryptamine (DMT), identified as endogenous ligand for sigma-1 receptors

Doctor-to-be Mariani blogged last Monday about a paper in Science where the endogenous ligand of the orphan sigma-1 receptor was identified as the hallucinogen, N,N'-dimethyltryptamine, or DMT. The work originated with the group of Arnold Ruoho and colleagues at the University of Wisconsin's Depts of Pharmacology and Physiology, together with a collaborator at the Isfahan University of Technology in Iran.

As an aside, what blows me away is that the first author on this publication, Dominique Fontanilla, is a graduate student in the UW Molecular and Cellular Pharmacology training program. The funding acknowledgment suggests that she was on an NIH institutional training grant and then scored her own individual predoctoral NRSA from the National Institute on Drug Abuse. It appears that she also has a background in synthetic chemistry that extends back to her Sigma Xi-recognized undergraduate work at Carleton College in Minnesota. If anyone is looking for a stellar postdoc candidate in this field (*cough* DrugMonkey), you'd better get in line now.

Anyway, as a neuroscientist, Laura tells the story far better than I can so you should go to her post to read the details.

Where a natural products cancer pharmacologist gets interested in this story is its intersection with plant-derived medicines - 25% of today's pharmaceuticals can be traced to natural sources, I recognize that the history of my discipline lies in the ethnobotany of indigenous cultures and their religious and ritual use of plant compounds with hallucinogenic effects of other activities in modulating the central nervous system. Hallucinogens used culturally in religious rituals are often called entheogens (loosely translated as "creating god within").

DMT is a naturally-occurring analog of serotonin, or 5-hydroxytryptamine, the neurotransmitter we try to manipulate with many antidepressant therapies. Many serotonin-like molecules, the most famous being LSD, have the potential to more dramatically influence our perception of reality than the neurotransmitter itself. Interestingly, we make very small but detectable amounts of DMT.

Where DMT is most famous, however, is as part of plant-derived hallucinogen cocktail called ayahuasca or hoasca used by the religious group, the União do Vegetal (more precisely the Centro Espírita Beneficente União do Vegetal or UDV.). I wrote awhile back about New Mexico-based UDV community that won the right to use their traditional plant brew containing DMT in a 21 Feb 2006 US Supreme Court decision citing protection of the group's activities under the 1993 Religious Freedom Restoration Act.

Here was my description at the time of the Ayahuasca tea:

The Hoasca hallucinogenic tea, more appropriately called Ayahuasca, is made from stems of the vine Banisteriopsis caapi together with the leaves of Psychotropia viridis (in Brazil, Peru, and Ecuador) or Diplopterys cabrerana (in Ecuador and Colombia). The latter two plants contain the hallucinogen, DMT, a serotonin analog that stimulates 5-HT2A receptors similar to LSD. However, DMT alone would normally be very quickly metabolized in the liver by monoamine oxidase A (MAO-A) such that little of the compound, if any, could get to the brain.

The key plant is B. caapi which is not hallucinogenic on its own. Instead, B. caapi contains beta-carboline compounds that inhibit the liver's ability to destroy the DMT. Most important among these is a compound called harmine, a well-characterized MAO inhibitor. In pharmacology, one would say that harmine potentiates the hallucinogenic effect of DMT. As a scientist, I am in awe of the South American cultures that discovered this concoction long before we had HPLCs and mass spectrometers.

The reader will note that I cited DMT's effect at serotonin 5-HT2A receptors. In other recent work, DMT has also been found to act on trace amine-associated receptors, or TAARs. However, it appears that a combination of in vitro and in vivo results, particularly behaviorial hypermobility studies in sigma-1 receptor knockout mice, is suggestive that DMT acts primarily on sigma-1 receptors.

I'm not qualified to delve too much into the therapeutic potential of these discoveries but the sigma-1 receptor may represent a unique opportunity to develop new drugs for schizophrenia and other debilitating psychotic disorders. For example, it was news to me from the Ruoho paper that the antipsychotic drug haloperidol (Haldol®) binds with very high affinity to sigma-1 receptors even though its therapeutic activity has long been attributed to its antagonism of dopamine at central dopamine D2 receptors.

Finally, Fontanilla et al. hypothesize that other dimethylated serotonin-like compounds may also exert their effects at sigma-1 receptors. For example, N,N'-dimethylserotonin, or bufotenine, is another compound with hallucinogenic activity that has been also been observed at elevated concentrations in the urine of patients with schizophrenia.

If the prefix "bufo" rings a bell to you, you'll think of the genus name for toads: bufotenine (and 5-methoxy-DMT) is secreted from the skin of many toads (Cane, Colorado River, Sonoran Desert toads). Toad licking or smoking of toad skin is a favorite hallucinogenic pastime of individuals in the desert southwest US, Mexico, and Australia.

I'll leave a scholarly treatment of toad licking and toad smoking for another day.

The fact that we are now finding a common mechanism for entheogens and hallucinogens reveals once again the awesome power of natural products in the discovery of the pathophysiology and pharmacotherapeutics of human diseases.

By Abel Pharmboy
February 23, 2009
Science Blogs
http://scienceblogs.com/terrasig/200...inogen_nn-.php

[RoboCodeine7610]

DXM also acts on the sigma receptors, acording to William White's FAQ.They should do some human studies with some kind of drug which antagonizes the sigma receptors and see if DMT was still Psychedelic.