serotonin2A
Bluelighter
- Joined
- Sep 13, 2014
- Messages
- 1,354
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 I think most of the relevant data may be unpublished, but some of the information is located in Jason Parrish's thesis: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-HT2A 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-HT2A 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-HT2A 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.
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