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SB-243213 acts as a selective inverse agonist for the 5-HT2C receptor.

The 5-HT2C receptor is one of many 5-HT receptors which are receptors that bind serotonin, and seems to play a major role in both suicide (some suicide victims have an abnormally high number of 5-HT2C receptors in the prefrontal cortex) and schizophrenia (activation of 5-HT2C receptors reduces mesolimbic nigrostriatal dopamine release (which conveys antipsychotic action)).

Chemicals which are commonly prescribed for major depressive disorder and schizophrenia are non-selective and affect a broad range of molecular targets (including other families of 5-HT2 receptors, and other targets) at varying binding affinities, while also producing a wide range of side effects related to those various molecular targets.

SB-243213 has better than 100x selectivity for 5-HT2C over all other receptor subtypes tested, and a longer duration of action compared to older 5-HT2C antagonist ligands.

It seems like a promising target for future research, but I can't find an example of it being tested in humans, but it seems to have had a healthy anxiolytic response in rats and a significantly beneficial response on the rat sleep profile, although this research is from almost 20 years ago.

Aside from distribution differences of 5-HT2C receptors in rat and human brains, what other differences could cause unexpected results and possible side effects if tested in a human?

One of the studies notes that positive results were seen at "10 mg/kg po" in rats, and having read the full text of one of the studies many tests were done with doses ranging from 1mg/kg to 10mg/kg, with tolerance studies up to 40mg/kg. Also, example routes and volumes for different animals are noted here.

How can an appropriate, initial test dosage be calculated for humans? The SDS from a manufacturer lists "Acute Toxicity: IPR-RAT TDLo: 0.63mg/kg". For a 250g rat, would that be ~15mg? For an 80kg human, would that be ~50g?

In what way would such a chemical be toxic? To the liver?

What can happen if a human takes such a dose of SB-243213?

If it hasn't been through a clinical trial, what are some of the risks?

From one of the articles above:

We have previously described the development of selective 5-HT2C receptor antagonists including SB-206553 and SB-242084...we have demonstrated an involvement of the 5-HT2C receptor in animal models of anxiety and depression and shown that such compounds do not possess either pro-convulsant or hyperphagic properties...Unfortunately these compounds were not suitable for progression into man for a number of reasons, including an interaction with cytochrome P450 enzymes. We have therefore developed SB-243213 as a selective 5-HT2C receptor antagonist (Bromidge et al., 2000) which does not interact with cytochrome P450 enzymes at concentrations up to 10uM. SB-243213 is currently in clinical development with potential for the treatment of a range of psychiatric diseases including anxiety, depression, and schizophrenia.

Essentially I'm looking for reasons why this might not be suitable for humans, or examples of possible side effects.

Why has this 20-year-old, apparently promising drug not proceeded beyond the clinical development mentioned?

There are 18 articles mentioning "SB-243213" on DeepDyve. I'll continue to update this post as I find more information. After reading all of the articles I plan to contact some of the authors if I can't find an answer this question by myself.

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    $\begingroup$ Welcome to Psychology & Neuroscience SE! "I'll continue to update this post as I find more information" Note that you are also allowed (and encouraged!) to answer your own question. At some point 'additional information' can form a (at least partial) answer. Thank you for a well-researched question! $\endgroup$ – Steven Jeuris Jan 20 at 14:16
  • $\begingroup$ Incredibly high selectivity might not be the best thing in a medication due to potential dosing errors. See fentanyl and its "super" derivatives... There is such a thing as serotonin syndrome (e.g. overdosing with SSRI). $\endgroup$ – SX welcomes ageist gossip Jan 30 at 20:52

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