Lumateperone v.s. Haloperidol ?

[MedicinalUser247]

I have a question. Lumateperone and Haloperidol are both Butyrophenones, but how similar are they to each other ?

 

[Skorpio]

I'm not quite sure. I have a gut feeling that Lumateperone is more selective/delicate, as it's a lot newer (wiki sez it's got a 60 fold higher 5ht2a affinity than any other targets).

There was a paper a few years ago that used antipsychotics as lead compounds for psychadelics and used the heterocycle on lumateperone to develop some non-psychadelic serotonin agonists (though they reported a psychadelic made from that backbone but didn't dwell on it, likely due to the funding source).

 

[Skorpio]

I made a post two years ago about the paper where they describe their process for designing 5HT2A agonists from antipsychotics. Extremely clever, and reveals a very solid grasp of the fundamentals of medicinal chemistry (as antagonists often have a pharmacophore to bind a target, and then enough bulk to prevent the receptor from moving into an active state.

Structure-based discovery of nonhallucinogenic psychedelic analogs

This group modified a bunch of anti-psychotic scaffolds removing bulk from them with the hypothesis that it would turn antagonists into agonists. Most of the compounds were non-psychadelic, but there was one scaffold that produced head twitch effects in rodents.

Called IHCH 7113

https://upload.wikimedia.org/wikipedia/commons/thumb/7/78/IHCH-7113.svg/1200px-IHCH-7113.svg.png

 

[DopeIsBeautiful]

Haloperidol is a first generation antipsychotic while lumateperone is i think a second one. It means that haloperidol is mostly a D2/D3 antagonist, while lumateperone possess some antagonistic action at the 5HT2A receptor. This action on 5HT2A was targetted in an effort to reduce the side-effects of first generation antipsychotics (like pyramidal symptoms). It worked kinda, but it came with new side-effets (metabolic for example).

 

[MedicinalUser247]

Yes, but I was wondering because there both Butyrophenones.

 

[Skorpio]

Yes, but I was wondering because there both Butyrophenones.

Based on the paper I posted, the butyrophenone moiety is what locks the receptor in an inactive conformation.

That team removed the butyrophenone and with some other small modifications they were able to generate a range of 5HT2A partial agonists (some non-psychadelic based on head twitch assay and bias, and some psychadelic).

I like the general principle that they follow, where an antagonist is considered to have both the pharmacophore which causes binding at a given receptor target, and a bulky part which jams the receptor.

Compare naloxone or nalyrexone and oxymorphone. The difference is that the antagonists have bulkier substituents on the nitrogen (an allyl or methyl cyclopropyl respectively), than the methyl of oxymorphone (you need at least a methyl though as the nitrogen needs to be tertiary to satisfy the morphine rule).

That additional bulk (obviously in exactly the right place) is sufficient to turn the oxymorphone pharmacophore into an antagonist.