5ht2b

[markosheehan]

hi i am looking for the safest 5ht2b/2a antagonist. i have seen that agomelatine can be bad for your liver. how safe is sarpogrelate?. also preferable one that does not crosss the blood brain barrier but i am not too picky on that. i am more concearned on the safety. i know this is hard to answer as there has not been much research done in the area so just if anyone can help me please do.

 

[kleinerkiffer]

Od -> N&PD

 

[Cotcha Yankinov]

When I previously investigated the matter I believe it was unknown whether or not Sarpogrelate crossed the BBB appreciably. If it doesn't cross the BBB, it would certainly be interesting. I suppose an experiment with MDMA + Sarpogrelate might reveal something about whether or not it crosses the BBB, because 5-HT2B blockade negates the effects of MDMA, but I would be cautious. I think 5-HT2B receptors are known to play a role in preventing the development of serotonin syndrome, so it may not be a good idea to disable them. Proceed with caution.

I believe Sarpogrelate also has reasonable antagonism of 5-HT2A and thus might also help with peripheral vasoconstriction.

 

[serotonin2A]

Sarpogrelate is a selective 5-HT2A antagonist, with almost 100-fold selectivity over 5-HT2B. It probably won't produce much 5-HT2B blockade at normal doses.

 

[Cotcha Yankinov]

I'm a bit confused, I was under the impression that severe vasoconstriction of the intracranial arteries can occur with excessive 5-HT2A agonism, and that migraine related pain had to do with vasodilation.

If Sarpogrelate, a migraine medication, is blocking 5-HT2A, could we speculate that Sarpogrelate's efficacy comes from inhibiting the excitatory neural activity (cortical spreading depression) that causes release of vasodilatory substances from Trigeminal neurons, and hence must either cross the BBB appreciably to affect neurotransmission, or that it may not cross the BBB and interferes with the release of vasodilatory substances from Trigeminal neurons more directly?

Or wouldn't it at least need to be able to cross the blood nerve barrier to interfere with release of vasodilatory substances from the Trigeminal neurons?

Just curious if Sarpogrelate could be used for psychedelic therapy patients who have peripheral vasoconstriction tolerance issues.

 

[serotonin2A]

I'm a bit confused, I was under the impression that severe vasoconstriction of the intracranial arteries can occur with excessive 5-HT2A agonism, and that migraine related pain had to do with vasodilation.

If Sarpogrelate, a migraine medication, is blocking 5-HT2A, could we speculate that Sarpogrelate's efficacy comes from inhibiting the excitatory neural activity (cortical spreading depression) that causes release of vasodilatory substances from Trigeminal neurons, and hence must either cross the BBB appreciably to affect neurotransmission, or that it may not cross the BBB and interferes with the release of vasodilatory substances from Trigeminal neurons more directly?

Or wouldn't it at least need to be able to cross the blood nerve barrier to interfere with release of vasodilatory substances from the Trigeminal neurons?

Just curious if Sarpogrelate could be used for psychedelic therapy patients who have peripheral vasoconstriction tolerance issues.

5-HT2A receptors are expressed in vascular smooth muscle and activation produces vasoconstriction. No need for an antagonist to cross the BBB.

 

[Cotcha Yankinov]

5-HT2A receptors are expressed in vascular smooth muscle and activation produces vasoconstriction. No need for an antagonist to cross the BBB.

Hence my confusion when supposedly vasodilation causes migraines - if 5-HT2A activation causes vasoconstriction, how does a 5-HT2A antagonist (that should cause vasodilation unless endogenous activation of 5-HT2Ar on vascular smooth muscle is negligible) help with migraines unless it is inhibiting the releasing of vasodilatory substances from Trigeminal neurons by altering neurotransmission/cortical spreading depression?

I suppose this is all assuming Sarpogrelate is effective for migraines, and is dependent on the type of migraine (maybe there are 5-HT2A related vasoconstriction dependent migraines?)

 

[serotonin2A]

Hence my confusion when supposedly vasodilation causes migraines - if 5-HT2A activation causes vasoconstriction, how does a 5-HT2A antagonist (that should cause vasodilation unless endogenous activation of 5-HT2Ar on vascular smooth muscle is negligible) help with migraines unless it is inhibiting the releasing of vasodilatory substances from Trigeminal neurons by altering neurotransmission/cortical spreading depression?

I suppose this is all assuming Sarpogrelate is effective for migraines, and is dependent on the type of migraine (maybe there are 5-HT2A related vasoconstriction dependent migraines?)

5-HT2A receptors are involved in peripheral hyperalgesia

 

[Cotcha Yankinov]

So Sarpogrelate could be binding to the nerves innervating the arteries and these small nerves may not be behind the blood nerve barrier very well, and thus Sarpogrelate may not necessarily need to cross the BBB to be an effective anti-migraine agent, and then could also be used to block the peripheral effects of 5-HT2A (and very mildly 5-HT2B) agonists?

 

[markosheehan]

could sarpogrelate be dangerous to take itself? can you get serotonin syndrome from taking sarpogrelate and a 5ht2b agonist. are there any other concearns of taking sarpogrelate and a 5ht2b agonist. is there a saffer 5ht2b antagonist?

 

[serotonin2A]

So Sarpogrelate could be binding to the nerves innervating the arteries and these small nerves may not be behind the blood nerve barrier very well, and thus Sarpogrelate may not necessarily need to cross the BBB to be an effective anti-migraine agent, and then could also be used to block the peripheral effects of 5-HT2A (and very mildly 5-HT2B) agonists?

Nerves innervating the vasculature, as well as cranial nerves, are outside of the BBB.