Can select 5-HT2b agonism cause death (NBOMes)? What antagonists might combat it?

[serotonin2A]

My point however is that the greater PLC activity seen in the NBOMe series (one was quoted at 65x PLA2 activity) could explain the vasospasm seen in humans.

The 65-fold selectivity figure was reported for TCB-2, which isn't a member of the NBOMe series. I think most of the relevant data may be unpublished, but some of the information is located in Jason Parrish's thesis:

EC50 values:

2C-I
PLC: 19 nM
PLA2: 23 nM

25I-NBOMe
PLC: 2.5 nM
PLA2: 8 nM

So it doesn't look like 2C-I or 25I-NBOMe is selective for the PLA2 pathway.

Interesting, hadn't heard that the PLC/PLA2 theory didn't work out. Mind pointing me in the direction of some literature on it, I haven't done any current reading on 5HT2A in ages.

One problem is that Nichols' prediction regarding the activity of TCB-2 didn't pan out:

http://pubs.acs.org/doi/full/10.1021/jm060656o

"We emphasize the fact that [TCB-2] is a functionally selective agonist at the 5-HT_2A receptor, having about 65-fold selectivity for the activation of the PLC signaling pathway over arachidonic acid release or 2-arachidonylglycerol (2-AG) production (Table 2). Although it is generally assumed that all 5-HT_2A agonists will possess hallucinogenic properties, a belief that has led to their neglect by the pharmaceutical industry, we challenge that assumption. We have previously shown that hallucinogenic activity is better correlated with production of arachidonic acid than with activation of PLC.¹⁶ If hallucinogenic properties are in fact associated with the production of arachidonic acid, or other eicosanoids, and not phosphoinositide turnover, it seems entirely possible that functionally selective 5-HT_2A agonists such as [TCB-2] might represent new therapies."

Unfortunately, TCB-2 did end up being hallucinogenic, and its potency roughly matches it's affinity. It is active at 5 mg po, and although it may be a little less potent than would be expected based on its 5-HT2A affinity, there is no where near the loss of potency that would be predicted based on its selectivity for PLC versus AA.

Of course, the PLC vs AA hypothesis doesn't live or die based on one prediction made for TCB-2. But the main reason why the AA signaling hypothesis was so attractive is that George Aghajanian's work had suggested that the effects of hallucinogens in cortex are mediated in part by a retrograde messenger. I think that was first suggested in the discussion of this article:

http://www.jneurosci.org/content/21/24/9955.long

But over time it became clear that a retrograde messenger probably wasn't involved in the effects of hallucinogens in the cortex. So the fact that there isn't any evidence that AA plays a role in mediating the cellular response to hallucinogens, coupled with the fact that potency for activating AA signaling does not predict hallucinogenic potency, calls into question the overall relevance of AA signaling to hallucinogen effects.

5HT2A is known to be the main vasoconstriting 5HT receptor in rats

Yup, 25I-NBOMe probably produces vasoconstriction via 5-HT2A. I don't know if the action of 25I-NBOMe is actually all that unique because DOB and Br-Dragonfly seem to cause the same problems. It may be that any highly efficacious 5-HT2A agonist has the potental to have these effects but that the particular pharmacological properties of 25I-NBOMe are such that it has a very low safety margin in some individuals.

 

[cybergollum]

What an interesting discussion... Please continue.
Bumped.

 

[endotropic]

So this is why I was so skeptical about lisuride not possessing hallucinogenic activity if it activates central 5-HT2A receptors. Not because I knew all of this about TCB-2 (thanks for that 2A) but because I've never seen another example in all of pharmacology where biased agonism causes a totally distinct reaction compared to a non-biased agonist. Graded differences sure, more or less of one effect or another, but never totally qualitatively different experiences. So I'm still confused about lisuride, but that's another discussion for another place maybe.

 

[serotonin2A]

So this is why I was so skeptical about lisuride not possessing hallucinogenic activity if it activates central 5-HT2A receptors. Not because I knew all of this about TCB-2 (thanks for that 2A) but because I've never seen another example in all of pharmacology where biased agonism causes a totally distinct reaction compared to a non-biased agonist. Graded differences sure, more or less of one effect or another, but never totally qualitatively different experiences. So I'm still confused about lisuride, but that's another discussion for another place maybe.

Another example in the 5-HT2A realm is ergotamine. I don't think people find it as interesting as lisuride for a few reasons, but it is definitely a 5-HT2A agonist and it is definitely not hallucinogenic. It has been used as a migraine medicine for the better part of a century (so it may have been used by millions of different patients) and I don't remember a single case of it being hallucinogenic. There are probably other examples that will appear in the literature over the next few years. Of course, you can't push the dose of ergotamine very high, but I suspect that isn't the reason why it has been found to be inactive.

That doesn't mean that biased agonism is the only potential explaination for why lisuride and ergotamine are not hallucinogenic. But the point I was trying to make is that they really do not appear to be active in humans...

 

[sekio]

If I were a betting man (I'm not), I'd be looking at the wackiness that is receptor dimerization: if I recall correctly it's an explanation for why some 5ht2a agonists are hallucinogenic and others are not & also why knocking out certain other non5ht receptors will kill psychedelic efficacy (e.g. certain mGluRs are hypothesized to form heterodimers with 5HT2A). Receptor heterodimerization is also known with CB1 and the opioid receptors. I also seem to recall that there's some mGluR agonists which are psychedelic-ish, though I'm not sure they've ever been used by humans.

 

[InterestingFACT]

If I were a betting man (I'm not), I'd be looking at the wackiness that is receptor dimerization: if I recall correctly it's an explanation for why some 5ht2a agonists are hallucinogenic and others are not & also why knocking out certain other non5ht receptors will kill psychedelic efficacy (e.g. certain mGluRs are hypothesized to form heterodimers with 5HT2A). Receptor heterodimerization is also known with CB1 and the opioid receptors. I also seem to recall that there's some mGluR agonists which are psychedelic-ish, though I'm not sure they've ever been used by humans.

I actually did some research on this topic for an animal cog. class I took recently. The gist of it is that receptor dimers do form between mGlu2 and 5ht2a and 5ht2b, but in in-vitro studies this didn't affect the signaling of either receptor at a surface level. Ie. Agonism of an mGlu2 receptor wouldn't suppress calcium mobilization by its dimerized 5ht2a receptor.

That being said, in-vivo studies pretty clearly show that mGlu2 agonism blocks the effects of 5ht2a agonists (One is being trialed as a novel antipsychotic right now, I believe), and mGlu2 antagonism increases head twitch response to hallucinogen exposure, so there's obviously a link between systems. Receptor co-localization also obviously exists, so it's very possible (I think likely) that mGlu2 interacts with 5ht2a somewhere farther down the intracellular cascade (maybe induction of a conformational change? I seem to remember reading something about changes in binding affinity), but once we move beyond their direct second messengers, dimerization seems more likely to be incidental than functional.

My personal theory is that the dimerization itself is non-functional, but that the psychedelic effects of 5ht2a agonists occur in cells that also express mGlu2. I remember reading that AMPA antagonists attenuate the effects of mGlu2 antagonists, and I've definitely noticed color saturation from sunifiram, so I wouldn't be remotely surprised if this turns out to be "common pathway" between glutamaturgic and serotonergic drugs.

I'm on my phone at the moment but later on I'll see if I can pull up some of the relevant research for you.

 

[serotonin2A]

I actually did some research on this topic for an animal cog. class I took recently. The gist of it is that receptor dimers do form between mGlu2 and 5ht2a and 5ht2b, but in in-vitro studies this didn't affect the signaling of either receptor at a surface level. Ie. Agonism of an mGlu2 receptor wouldn't suppress calcium mobilization by its dimerized 5ht2a receptor.

You have the second point wrong--Gonzalez-Maseo et al are claiming that mGlu2 suppresses the signaling response to 5-HT2A. There was also a paper by Molinaro showing that a mGlu2 agonist can block IP hydrolysis induced by DOI, so I think it is pretty clear that mGlu2 can modulate 5-HT2A-induced signaling.

http://www.ncbi.nlm.nih.gov/pubmed/19439499

What isn't clear is whether these signaling interactions are due to a direct physical interaction between the receptors.

That being said, in-vivo studies pretty clearly show that mGlu2 agonism blocks the effects of 5ht2a agonists (One is being trialed as a novel antipsychotic right now, I believe), and mGlu2 antagonism increases head twitch response to hallucinogen exposure, so there's obviously a link between systems. Receptor co-localization also obviously exists, so it's very possible (I think likely) that mGlu2 interacts with 5ht2a somewhere farther down the intracellular cascade (maybe induction of a conformational change? I seem to remember reading something about changes in binding affinity), but once we move beyond their direct second messengers, dimerization seems more likely to be incidental than functional.

By their proposal, all the things you mentioned would be mediated by direct physical interactions between the receptors.

My personal theory is that the dimerization itself is non-functional, but that the psychedelic effects of 5ht2a agonists occur in cells that also express mGlu2. I remember reading that AMPA antagonists attenuate the effects of mGlu2 antagonists, and I've definitely noticed color saturation from sunifiram, so I wouldn't be remotely surprised if this turns out to be "common pathway" between glutamaturgic and serotonergic drugs.

I'm on my phone at the moment but later on I'll see if I can pull up some of the relevant research for you.

For an extensive counterpoint on the role of the heteromers, see:

http://www.ncbi.nlm.nih.gov/pubmed/22300836

http://www.ncbi.nlm.nih.gov/pubmed/23466331

They make some pretty good counterpoints. One issue is that the receptors may be able to interact if you allow them to associate in an experiment, but they may never have that opportunity in the brain. Receptors and other signaling effectors are usually confined within specific microdomains of a cell. 5-HT2A and mGlu2 may be expressed in the same cells and even in the same part of the cell, but that doesn't mean they will be able to make physical contact. They also show that mGlu2 is relatively promiscuous and can form heteromers with a variety of GPCRs, which makes it more likely that these direct interactions are meerly an artifact. I'm not trying to argue that the heterodimers do not mediate the intetactions, only that it is extremely difficult to conclusively prove these things in vivo.