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what do sigma receptors do?

T

toxide

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Mar 21, 2006
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I'm sure this Q has been pondered on 4 a while but I was wondering if anyone has any recent info on this.

For instance noscapine appears to be a sigma agonist. I noticed info on it in the dxm faq mentioning it with other dissociative drugs but it doesnt seem to effect nmda and has barely any affinity for opiate receptors.

wikipedia mentions it's effects as like being on a drunken dxm high and says that it's a sigma agonist and has been used recreationally. However this is the 1st I've heard of this and there seems to be no info on any of this, and there's a "this artical needs a rewrite" attached to the artical.

I was very interested in this but not sure what to expect really, does anyone know more about this?
 
Never known anyone to take any selective sigma agonists but from the literature it seems that they would produce a dissociative hallucinogen effect something along the lines of kappa agonists (e.g. salvia) or NMDA antagonists (e.g. ketamine). So yeah probably somewhat like DXM.

On a different note though, sigma agonists seem to be pro-convulsant; heroin, cocaine and PCP are all sigma agonists in addition to their primary mechanisms of action and all three can sometimes produce convulsions which are blocked by sigma antagonists like rimcazole.
 
This seems to sum up current knowladge of sigma receptors:

Curr Med Chem. 2003 Oct;10(20):2073-80.

Understanding the Molecular Mechanism of Sigma-1 Receptors: Towards A Hypothesis that Sigma-1 Receptors are Intracellular Amplifiers for Signal Transduction.

Su TP, Hayashi T.

Cellular Pathobiology Unit, Cellular Neurobiology Research Branch, Intramural Research Program, National Institute on Drug Abuse, NIH, DHHS, 5500 Nathan Shock Drive, MD 21224, Baltimore, USA. [email protected]

Although sigma receptors were discovered in 1982, the biochemical and physiological roles of sigma receptors have just begun to unveil. Sigma receptors are non-opioid, non-phencyclidine receptors that contain two subtypes: sigma-1 and sigma-2 receptors. The sigma-1 receptor has been cloned and its sequence does not resemble that of any mammalian protein. Sigma-2 receptors have not been cloned. The focus of this review will be on sigma-1 receptors. Sigma-1 receptors contain 223 amino acids and reside primarily at the endoplasmic reticulum. Sigma-1 receptors exist mainly in the central nervous system, but also in the periphery. Sigma-1 receptor ligands include cocaine, (+)-benzomorphans like (+)-pentazocine and (+)N-allyl-normetazocine (or (+)-SKF-10047), and endogenous neurosteroids like progesterone and pregnenolone sulfate. Many pharmacological and physiological actions have been attributed to sigma-1 receptors. These include the regulation of IP3 receptors and calcium signaling at the endoplasmic reticulum, mobilization of cytoskeletal adaptor proteins, modulation of nerve growth factor-induced neurite sprouting, modulation of neurotransmitter release and neuronal firing, modulation of potassium channels as a regulatory subunit, alteration of psychostimulant-induced gene expression, and blockade of spreading depression. Behaviorally, sigma-1 receptors are involved in learning and memory, psychostimulant-induced sensitization, cocaine-induced conditioned place preference, and pain perception. Notably, in almost all the aforementioned biochemical and behavioral tests, sigma-1 agonists, while having no effects by themselves, caused the amplification of signal transductions incurred upon the stimulation of the glutamatergic, dopaminergic, IP3-related metabotropic, or nerve growth factor-related systems. Thus, it is hypothesized that sigma-1 receptors, at least in part, are intracellular amplifiers creating a supersensitized state for signal transduction in the biological system.

PMID: 12871086
Click to expand...
 
As far as I am aware, the Jury is still out on WTF sigma-1 receptors do. I wouldn't bet all my funds that it was a signal amplifier just yet.
 
Sigma receptor info seems hard to come by. I'll sometimes find a list of drugs that have an affinity for sigma receptors but they won't say if their antagonist , reverse agonists , agonists , etc A few sites say that sigma is a opiate sub-type and others say it definitely is not.

Here's a paragraph from the wikipedia article:

The sigma receptors σ1 and σ2 were once thought to be a type of opioid receptor, because the d stereoisomers of the benzomorphan class of opioid drugs had no effects at μ, κ, and δ receptors, but reduced coughing. However, pharmacological testing indicated that the sigma receptors were activated by drugs completely unrelated to the opioids, and their function was unrelated to the function of the opioid receptors. For example, phencyclidine (PCP), and the antipsychotic haloperidol may interact with these receptors. Neither phencyclidine nor haloperidol have any appreciable chemical similarity to the opioids. When the σ1 receptor was isolated and cloned, it was found to have no structural similarity to the opioid receptors. At this point, they were designated as a separate class of receptors. The functions of these receptors are poorly understood and any endogenous ligands have yet to be identified. Sigma receptors may induce hallucinogenic effects and also may be responsible for the paradoxical convulsions sometimes seen in opiate overdose. Drugs known to be sigma agonists in addition to their major mechanisms of action include cocaine, heroin, PCP and dextromethorphan, however the exact role of sigma receptors is difficult to establish as many sigma agonists also bind to other targets such as the κ-opioid receptor and the NMDA receptor. In animal experiments, sigma antagonists such as rimcazole were able to block convulsions from cocaine overdose. Sigma antagonists are also under investigation for use as antipsychotic medications.

http://en.wikipedia.org/wiki/Sigma_receptor#The_.CF.83_receptor
 
Dude do you just come on here to relay info from a dude into chemistry here, or talk about research chemicals and illegal drugs that you supposedly synth, and to have a go at people? :p
 
Psyly seems to have summarized all I know on the subject into a nice condensed and easy to read account.

Also, it deserves mention that methamphetamine has sigma activity (Matsumoto et. al). The importance of all this being that knowledge of this receptor might lead to various applications like in treating or helping prevent stimulant overdose etc or in helping rationalize why some drugs are safer than others etc. However it seems like a grey area where not all that much is known about it relative to some of the more popular receptors.
 
I don't know much about sigma receptor activity, but it does seem to me that it might in some way, have something to do with drug induced psychosis along with the dopaminergic system. I'm most probably way off the mark, but every drug I've looked at that has dopaminergic activity and acts as an agonist at sigma receptors seems to produce symptoms very like those of psychotic mental illness either from long term or short term use.

I know heroin is cited as a weak sigma agonist, but mu agonism seems to reduce active psychotic symptoms - probably why lots of people with a psychotic illness are drawn to mu agonist opioids as they 'damp down' a fair few of the most disturbing symptoms (obviously not candidates for use as an antipsychotic in clinical treatment though!)
 
Sigma1 Antisense treatments block cognitive, behavioral and amnestic effects of NMDA antagonists. σ-1 antagonists act as potent neuroprotectives against stroke, TBI by inhibition of inducible nitric oxide synthase. Sigma1 agonists enhance cocaine euphoria & dopamine relase, the oposite effect is acheived by σ-1 antagonists which are being considered as potential therapeutic agents for Coc. & meth addiction. Sigma1 and Sigma2 ligands effects on dopamine require PKC(protein kinase Calpha/gamma)

Although certain σ-1 receptor ligands show antipsychotic actions, the roles of σ-1 receptors in memory, cognition and depression have been examined more extensively. σ-1 agonists also exert antidepressant-like actions in the forced swimming test faster than TCAs.

σ-1 receptors have been cloned (Hanner et al., 1996), and their biological and physiological roles have been more exstensively examined; σ-2 receptors have not. The σ-1 receptor gene is located on human chromosome 9, band p13, and it encodes 25 kDa membrane proteins that have no homology to any mammalian protein (Hanner et al., 1996; Prasad et al., 1998). Sigma-1 receptors are intracellular receptors mainly localized on the endoplasmic reticulum, and they dynamically translocate inside cells (Hayashi and Su, 2003a, 2003b).

Sigma-1 receptors are expressed in specific regions of the brain such as layers of the cortex, hippocampus, hypothalamic nuclei, substantia nigra and Purkinje cells in the cerebellum (Heroux et al., 1992; Kitaichi et al., 2000).

Although the exact molecular action of σ-1 receptors is still unclear, a number of studies have demonstrated that they play a role as a modulator of ion channels (K+ channels; N-methyl-D-aspartate receptors [NMDA]; inositol 1,3,5 trisphosphate receptors) (Hayashi and Su, 2001; Hayashi et al., 2000; Monnet et al., 1992; Wilke et al, 1999). Studies also suggest that σ-1 receptors regulate lipid transport/metabolism, neuritogenesis, cellular differentiation and myelination in the brain (Hayashi and Su, 2004b, 2003b).
 
Well I guess that answers(or dusn't answer) my Q. But Does anbody have info on the effects of NOSCAPINE aka narcotine like 1st hand info or atleast knowledge of others who've dun it
 
Sertraline is a sigma agonist with 5% of its SERT affintiy (says wiki); therefore I doubt sigma agonism causes any serious dissociative effects or psychosis.
 
Stahl's Essentials of Psychopharmacology says there is sigma affinity also. I haven't found out though if it is an agonist, reverse agonist, antagonist etc. Haloperidol has affinity for sigma also. I don't know if it has any relationship to theraputic effects.
 
Your logic is a little out there rnd.id. If Sertraline is a sigma agonist with 5% of its affinity for the SERT, then assuming sertraline is dosed to bind to 50% of SERTs, then sertraline will be bound to about 4.7% of receptors. Which is pretty insignificant.

Haloperidol has significant sigma affinity, about 1nM, but it is an antagonist there.
 
BilZ0r said:
Your logic is a little out there rnd.id. If Sertraline is a sigma agonist with 5% of its affinity for the SERT, then assuming sertraline is dosed to bind to 50% of SERTs (...)
Click to expand...

Well, apparently 50% SERT inhibition corresponds to 9mg / day. The maximum recommended daily dose is 200mg.
 
Where did you get that from? I was actually a bit out before, but was doing 50% occupancy for the ease of the maths. It's my understanding that 80% occupancy is the usual amount. That makes the amount of binding about 16%. Still, do we even know if it is an agonist?

Voineskos AN, Wilson AA, Boovariwala A, Sagrati S, Houle S, Rusjan P, Sokolov S, Spencer EP, Ginovart N, Meyer JH.
Serotonin transporter occupancy of high-dose selective serotonin reuptake inhibitors during major depressive disorder measured with [11C]DASB positron emission tomography.
Psychopharmacology (Berl). 2007 Sep;193(4):539-45.

Meyer JH, Wilson AA, Sagrati S, Hussey D, Carella A, Potter WZ, Ginovart N, Spencer EP, Cheok A, Houle S.
Serotonin transporter occupancy of five selective serotonin reuptake inhibitors at different doses: an [11C]DASB positron emission tomography study.
Am J Psychiatry. 2004 May;161(5):826-35

By my reading, sertraline binds to the sigma1 receptor with a ki of 57nM (and >1uM for sigma2)[2], while it binds to the SERT with a Ki of 1nM (PDSP average, excluding the 2 obviously wrong results). That puts the occupancy down to 7%.

--EDIT--
Oh, I see we do know its an agonist. Though Im curious is those kind of definitions make sense on such a bizarre protein, i.e. does it even have an endogenous ligand.
 
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Apparently, sigma ligands may also have anti-cocaine activity:

Trifluoromethoxyl Substituted Phenylethylene Diamines as High Affinity σ Receptor Ligands with Potent Anti-Cocaine Actions
Smith, T. A.; Yang, X.; Wu, H.; Pouw, B.; Matsumoto, R. R.; Coop, A.
J. Med. Chem.; (Brief Article); 2008; 51(11); 3322-3325. DOI: 10.1021/jm7013666. http://pubs.acs.org/cgi-bin/searchRedirect.cgi/jmcmar/2008/51/i11/abs/jm7013666.html
Click to expand...

That means that sigma receptors are somehow involved in the rewarding properties of cocaine.
 
Bumping this, instead of making a new one on it... I am trying to read everything I can about this without article privileges, though I have checked Nichols account of DMT being a ligand for sigma.

Currently I want to investigate the effects arylcyclohexylamines can have and disect their pharmacological ranges, from NMDA antagonism to mu to DRD2, etc. and try to get a feeling of what happens if a compound has a higher or lower sigma component.

How good an example is DXM with it's supposed sigma plateau? Might sigma have associations with derealization such as extended DXM redosing or with DMT? If we take that to happen with excessive activity at the site does that mean that sigma might play a role hinging our memory and sense of reality together in a way, by either it's own endoligand household, mediation of other receptor mechanisms or both?

If anyone want to shine some light on this or post some new insights that changes the way we look at this at some point "orphaned" receptor, that would be great.
And if I talk out of my ass with ideas or presumptions based on poor understanding, please excuse me. :) I try to do my best.
 
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