Tight binding 5ht2a antagonists to counteract 25x overdose

[IGNVS]

Ive heard of some extremely tragic overdoses on the 25 series of psychedelics, and how there is no treatment for people with seizures and organ failure when they arrive in the hospital still tripping balls... I propose reseaech for antagonists with higher binding affinity that are metabolised faster than the 25 drugs to displace them until new receptors have a chance to work wothout excess 25 being present to grab them too. What antagonists are known and what medicinal chemistry could be used to enhance affinity?

 

[sekio]

How about not taking a whole fuck ton of nanomolar-affinity serotonin agonists in the first place.

There are plenty of treatments for people who arrive in hospital tripping. Benzodiazepines, high strength antipsychotics, dantrolene, etc. And there's not even a lot of evidence that 5-ht2a activation alone causes death or organ failure.

Why do some drugs like 2c-t-7/21 and DOx cause malignant hyperthermia etc whereas you do not hear about it very often from e.g. lsd and 2c-c?

 

[endotropic]

Ketanserin is a compound with high affinity 5-HT2a antagonism that's already in clinical use, so it would be a lot easier to move forward than something off the bench.
http://en.wikipedia.org/wiki/Ketanserin

Also I don't think you'd want a compound that's metabolized faster than the 25x's, because that would mean it would wear off sooner, and with the 25x still present you'd be right back where you started.

 

[IGNVS]

5meo npbrt looks like a selective antagonist with a ki less than 1nm, however I cant find a link to the article for the actual value. Hopefully its less than .044 :/ ... Think a 2meo on the ring would bind stronger than the 4br?

 

[IGNVS]

Firat off its never advised to eat a stupid ammount of rc, but with its prevalence online and recently in the streets, uneducated individuals have started being down right reckless, and its enevitability as predicted is comming to fruition. It makes me irate. This is about harm reduction. that said, I was afraid agonism alone wouldnt be the cause of organ failure, gcprs oligomerize in a unique way for each agonist, even to the same receptor.. Perhaps finding drugs to break up specific combinations instead of just antagonists should be employed. Or downstream effects studied for new targets... Lots of interesting reseaech ahead there. As far as a shorter durration, it would be to avoid antagonizing them longer than the initial metabolism of the 25... Just an idea. I supose binding of metabolites would also contribute to the effects. anyone with some more experience want to chime in and post considerations?

 

[Aetherius Rimor]

The toxic effects of 25x drugs is unrelated to it's 5HT2a agonism. It's related to the fact it skyrockets blood pressure and heart rate to unsafe levels.

Their binding profiles are more in line with a psychedelic stimulant, rather than just plain psychedelic. And those stimulant properties, coupled with the inability to perceive reality normally increase chance of injury.

 

[Cortexiphan]

The toxic effects of 25x drugs is unrelated to it's 5HT2a agonism. It's related to the fact it skyrockets blood pressure and heart rate to unsafe levels.

Their binding profiles are more in line with a psychedelic stimulant, rather than just plain psychedelic. And those stimulant properties, coupled with the inability to perceive reality normally increase chance of injury.

Can you provide some data to support that? To the best of my knowledge 25X-NBOMe's are currently some of the most selective 5-HT2A agonists. They bind 2B and 2C too, but to the same degree as any other 2C-X/DOX and that hardly makes them stimulants.

 

[Solipsis]

In PD the point was made that these NBOMe compounds produce local anaesthesia which may be caused by sodium / calcium channel blocking (assumption #1), and that local anaesthetics that do this tend to be unsafe to the cardiovascular system (assumption #2: this may be the real cause of toxicity) so perhaps treatment of an overdose lies in something like cardiopulmonary resuscitation and lipid infusion (assumption #3: related treatments, that are easily found by a globally used search engine, may work).

 

[Aetherius Rimor]

Can you provide some data to support that? To the best of my knowledge 25X-NBOMe's are currently some of the most selective 5-HT2A agonists. They bind 2B and 2C too, but to the same degree as any other 2C-X/DOX and that hardly makes them stimulants.

Appears I might be mistaken. I assumed due to the effects on the cardiovascular system, that it must have a stimulant effect. Apparently though 5HT2a does play a role in vasoconstriction.

I need to look more into this.

Research paper on 5HT2a antagonists reversing 5HT2a vasoconstriction: http://www.ncbi.nlm.nih.gov/pubmed/18430065

These results demonstrate that, in human ITA, 5-HT-induced vasoconstriction is mediated by activation of both 5-HT(2A) and 5-HT(1B) receptors. Thus, when the human ITA is used as an arterial graft, a combination of 5-HT(2A) and 5-HT(1B) receptor antagonists would appear to be most useful to prevent 5-HT-induced vasospasm.

 

[Epsilon Alpha]

In PD the point was made that these NBOMe compounds produce local anaesthesia which may be caused by sodium / calcium channel blocking (assumption #1), and that local anaesthetics that do this tend to be unsafe to the cardiovascular system (assumption #2: this may be the real cause of toxicity) so perhaps treatment of an overdose lies in something like cardiopulmonary resuscitation and lipid infusion (assumption #3: related treatments, that are easily found by a globally used search engine, may work).

I'm not too convinced the NBOMe compounds would make potent sodium channel blockers, as they lack too may elements of the most widely accepteed backbones.
http://en.wikipedia.org/wiki/Local_anesthetic

 

[Torabora]

Well we dont know how those people get threated maybe they never got and 5ht2a antagonist and this is really the key point?

the vasconstriciton could really be the cause like it was with those br-dragonfly-deaths

 

[nuke]

In PD the point was made that these NBOMe compounds produce local anaesthesia which may be caused by sodium / calcium channel blocking (assumption #1), and that local anaesthetics that do this tend to be unsafe to the cardiovascular system (assumption #2: this may be the real cause of toxicity) so perhaps treatment of an overdose lies in something like cardiopulmonary resuscitation and lipid infusion (assumption #3: related treatments, that are easily found by a globally used search engine, may work).

Is there experimental data to support this?

 

[Epsilon Alpha]

I'm almost positive that NBOMe compounds would not be potent Na channel blockers, Ca channels are a bit more promiscuous regarding ligand binding so they might be a target. But, in any case we're looking at low nanomolar affinity for a particular target given the doses. Perhaps it's just a horribly biased 5HT2A ligand?

5HT2A activation with a full agonist doesn't seem like its something your heart likes too much:
http://circres.ahajournals.org/content/98/7/931.short

 

[MeDieViL]

Seroquel will reverse overdose of psychedelics that bind less selective to the 5HT2A receptor.

 

[doxneed2c-me]

I thought it was well known they already do
http://en.wikipedia.org/wiki/Tolazoline
Seems that this combined with fluid replacement is part of the regimen for treating vasocontriction and organ failure related to overdose on certain compounds. It seems treating organ failure is done similarly for any given scenario.

 

[paranoid android]

Seroquel will reverse overdose of psychedelics that bind less selective to the 5HT2A receptor.

Risperidone is a much stronger 5ht2a receptor antagonist then seroquel is.

 

[slo mo]

Risperidone is a much stronger 5ht2a receptor antagonist then seroquel is.

I read that hospitals use 12mg of cyproheptadine for serotonin syndrome as noted below from the link

http://www.uptodate.com/contents/serotonin-syndrome

Cyproheptadine is available in 4 mg tablets or 2 mg/5 mL syrup [8]. When administered as an antidote for serotonin syndrome, an initial dose of 12 mg is recommended, followed by 2 mg every two hours until clinical response is seen. Cyproheptadine is only available in an oral form, but it may be crushed and given through a nasogastric tube.

Cyproheptadine may lead to sedation, but this effect is consistent with the goals of management [1]. Furthermore, as a nonspecific serotonin antagonist, cyproheptadine may produce transient hypotension due to the reversal of serotonin-mediated increases in vascular tone. Such hypotension usually responds to intravenous fluids. Cyproheptadine is rated category B for safety in pregnancy by the US Food and Drug administration (FDA) (table 5) [8].

Definitive evidence of cyproheptadine's effectiveness is lacking. A small study used PET scan to assess 5-HT2 blockade in two volunteers after taking cyproheptadine (12 mg and 18 mg per day for six days). At 12 mg/day, there was 85 percent blockade and at 18 mg/day there was over 95 percent blockade of 5-HT2 receptors in the prefrontal cortex [16]. In addition, many reports describe the successful use of cyproheptadine to treat serotonin syndrome [15,17-22]. The majority of these patients received cyproheptadine at an initial dose of 8 mg, while fewer patients responded to as little as 4 mg and some had no response to as much as 16 mg.

Other antidotes — Antipsychotic agents with 5-HT2A antagonist activity, such as olanzapine and chlorpromazine, have been considered for antidotal treatment, but their efficacy is unproven and we do NOT recommend their use [1]. Chlorpromazine can cause orthostatic hypotension, although this is generally not an issue with serotonin syndrome, in which hypertension is common. Chlorpromazine can also increase hyperthermia.

Treatment with propranolol, bromocriptine, or dantrolene is NOT recommended. Propranolol has a long duration of action, may cause prolonged hypotension, and can mask tachycardia that can be used to monitor the effectiveness of treatment. Bromocriptine, a serotonin agonist, may exacerbate serotonin syndrome [1]. Dantrolene has no effect on survival in animal models