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As someone with a background in organic chemistry, I have a silly nit to pick with the phrasing "LSD-like molecules" These molecules look nothing like LSD! Str
by isoprophlex 4y ago
As someone with a background in organic chemistry, I have a silly nit to pick with the phrasing "LSD-like molecules"
These molecules look nothing like LSD! Structurally they are as different from eachother as a dog is to a flying squirrel.
Of course they act like LSD by binding to 5HT2a. This is absolutely terribly pedantic and probably only applies to the mind of someone who wants to see the molecules first, and the rest of the research later, but I would have preferred "Molecules that act like LSD can counter depression without the trip"
- tpm 4y agoOr even "Molecules that act like LSD in regards to 5ht2a can counter depression without the trip". Because LSD is also active at other targets, and presumably those new molecules too.
- ithkuil 4y agoOr perhaps they don't, that's why you get some effects and not others (as desired)?
- tpm 4y agoThe probably strongest and most selective currently known 5ht2a agonist, 25I-NBOMe, is a psychedelic, and also (unlike LSD, which is less strong and less selective), much much more toxic and user reports say that the effects, both on body and mind, are much worse. So this is a complicated topic and I look forward to reading user reports from these new molecules, if they decide to test them.
- gavinray 4y agoEh, I wouldn't call the mental effects of NBOMe's objectively worse than say LSD -- just different Now, the body load/vasoconstriction + other physical effects, definitely. You can always tell the NBOMe is kicking in when you get shuttery cold from vasoconstriction and have a weird motor rigidity. Also FWIW, there are more potent agonists than NBOMe. I know of at least one discovered by Nichols' lab that they refused to publish for fear of use as an aerosolized bio-weapon.
- carrychains 4y agoYour preference is unnecessarily pedantic and logically reduces in specificity to the exact phrasing that peeves you.
- isoprophlex 4y agoDefinitely!
- lifeisstillgood 4y ago"This is absolutely terribly pedantic and..." Don't worry. You're in the right place :-)
- motbus3 4y agoDon't worry Y in Ycombinator is for pedantic XD
- bfung 4y agoHaha, I feel ya - As a computer/tech person, when business people say real-time, or AI (when they just want simple statistics) I get the same annoyance and react with the pedantism (you don't need REAL-time, just sub-second latency). But for the non-experts and layfolk, many KNOW what LSD does, but none of us know what 5H... yup. =)
- throw827474737 4y agoBeing pedantic (and a smartass) the same, "real-time" original definition is that some calculation/reaction of the system is guaruanteed to be always bounded and within the system rqequirements (usually for it not to fail). So depending in the use case and application, real-time can be sub-second, or even seconds/minutes. E.g. if the instagram folks require likes to happen in real-time for all users around the world that is fine to be within seconds, but a safety critical application in a car must respond within milliseconds.. "you don't need REAL-time, just sub-second latency" in general does not make much sense, sounds more like this application real-time requirements just lie in the sub-second resolution region?!
- SirRuthven 4y ago> react with the pedantism… Some pedant has to say it: shouldn’t that be “pedantry”?
- bfung 4y agoLOL - true, thx.
- erikpukinskis 4y agoSimple statistics can be AI. AI just stands for Artificial Intelligence. An if-statement can be AI. Are you thinking of machine learning?
- xdfgh1112 4y ago"LSD-like" can mean "acts like" just as well as "looks like", so you're being hyperpedantic.
- ekianjo 4y agoor alternatively the headline is just super clickbaity by adding LSD when it was not needed.
- alehlopeh 4y agoSo using LSD in a title makes it clickbaity? Come on, that’s ridiculous. Don’t squeeze the life from that term by applying it to anything you don’t like.
- Retric 4y agoThe comparison to LSD is sensationalized and misleading making it clickbait even if the link is not deceptive. https://en.wikipedia.org/wiki/Clickbait https://en.wikipedia.org/wiki/Clickbait
- ekianjo 4y ago> So using LSD in a title makes it clickbaity Yes alluding to something illegal makes it clickbaity.
- quietbritishjim 4y agoI guess it's like the question of: could you say an SSD is "hard drive-like" even though it works totally differently? I would say you validly could.
- boloust 4y agoWhile you could say a drug is "LSD-like" because one of the many receptors it targets is also targeted by LSD, that would be more akin to saying a keyboard is "hard-drive-like" because they both plug into a computer. Biology is extremely complex, and even drugs that have similar receptor binding profiles can have very different effects. Most drugs will have action across a wide range of receptors. There are a multitude of drugs that target the 5-HT2A receptor, including the most common antidepressants and antipsychotics, for example.
- kaoD 4y agoI'm curious about this and someone here might know. Why do they bind to the 5HT2a receptor yet not cause trips? I always assumed the difference in strength between, say, DMT and psilocybin was because DMT was "more agonist" (pardon the layman terms). Do these molecules intrinsically not cause trips, or is this more akin to microdosing? Would a higher dose of these molecules cause a trip?
- valec 4y agodifferent ligands can bind to the same receptor in different ways and cause different signaling cascades. look up "biased agonism"
- tux3 4y agoIt's fascinating how Nature effortlessly creates these leaky abstractions, completely opposite to how we design systems, and makes good use of the constant layering violations where we would see unmaintainable code that we can't wrap our heads around. When we design signaling mechanism, they deal with the layer below while presenting a simpler digital interface to the layer above. Your Ethernet PHY has to care about electrical details, but to the IP stack it's just a stream and sink of bytes. No weird side-band edge cases effects, like if the IP stack could affect DC balance by changing the mix of 1s and 0s it sends out. But those G protein-coupled receptors — or whatever it is — it seems like if you don't want to miss important side-band edge case signals, you really have to model them as this 3D structure that threads through the membrane 7 times, that you can jiggle on one side to change the shape it has on the other side. The receptor-agonist abstraction makes total sense from a human perspective (and it's a good and useful model), but at the end of the day the Wikipedia lists nine different types (partial, super-, inverse, co-, irreversible, biased, ..) of agonists, multiple of which can apparently apply to a single ligand ("can concurrently behave as agonist _and_ antagonists at the same receptor, depending on effector pathways or tissue type"). Nature seems to have absolutely no preference for clean abstractions, and I don't know how to feel about that, but it's fascinating to me. Maybe my horrible code is actually universally optimal under a non-human optimizer =) Or maybe it's just intrinsically hard to make clean abstraction out of chemistry? I wonder if it _would_ be beneficial for a large system like the body to be built out of cleaner (less powerful) abstractions that don't expose all their internal details, but maybe stochastic DNA mutations with natural selection isn't a good enough optimizer to find that place in humanity genomespace? Death is so out of style compared to Adam and SGD.
- 9991 4y agoThey didn’t say “LSD-shaped”. There are lots of ways to be “-like”, and one is acting in a similar manner. Your training is blinding your thinking.
- mseidl 4y agoMaybe a flying squirrel compared to a flying dog would be better?
- doctor_eval 4y agoWell, they are both mammals, so at some level a dog actually is squirrel-like.
- erikpukinskis 4y agoA dog is extremely squirrel-like. Compared to a fish or a fungus or a sequoia a squirrel and dog are basically the same.
- amelius 4y ago> These molecules look nothing like LSD! Who said "look"? You're being pedantic about your own interpretation.
- sva_ 4y agoWhere can you see these molecules? I wonder how they look like compared to serotonin and some tryptamines https://i0.wp.com/sitn.hms.harvard.edu/wp-content/uploads/2015/03/Fig-1-Psychedelics.jpg https://i0.wp.com/sitn.hms.harvard.edu/wp-content/uploads/20...
- gpcr1949 4y ago(I have a background in organic chemistry as well) I somewhat disagree with this. Measuring chemical similarity is notoriously difficult, see these two interesting blog posts from a cheminformatic angle [0][1]. The molecules are not only pharmacologically similar but even chemically at least somewhat similar, perhaps in the same way a dog has much more similarities with a flying squirrel than with, let's say a church. I would argue the main active molecule [2] is relatively similar to LSD (compared to other well known psychedelics) due the presence of the tetrahydropyridine unit, which is also present in LSD, albeit connected to the 3 position of the indole in a different way. Also, there is a pharmaco*phor*ic similarity: positively charged N and 5-6 fused aromatic ring oriented in the same way with some degree of rigidity (though you could argue this is just a roundabout way to bin it in a category of 5ht2a binders). So in this way, I feel that it has something like an LSD-based design philosophy to it. Quantitatively, making use of one of the most common similarity metrics, the Tanimoto similarity of ECFP4 fingerprints, the similarities to LSD, psilocin, DMT and mescaline are respectively 0.17,0.15,0.18 and 0.07. In other words, the similarity is low to all compounds and the indole derivatives are about equally far removed from the compound from TFA, although a bit closer than mescaline. The numbers probably rather follow your line of reasoning. Finally, I'd also like to remark that I consider the fact they generated quite novel chemical matter a plus: most of the people working on generating new 5HT2A agonists are currently using quite conservative classic SAR approaches, for example creating constrained (e.g. Lophora's azetidines) or deconstructed versions (e.g. Delix's ring opened LSD variants and ibogaine analogs) of better known compounds, or even just prodrugs of known compounds (Field trip's FT104 is a 4-HO-DIPT prodrug). This will also make it easier for them to fight patent challenges if this series of compounds will lead to a clinical candidate. [0] http://www.dalkescientific.com/writings/diary/archive/2020/09/08/drug_control_law_and_molecular_similarity.html http://www.dalkescientific.com/writings/diary/archive/2020/0... [1] http://www.dalkescientific.com/writings/diary/archive/2020/09/10/US_v_brown_v_tanimoto.html http://www.dalkescientific.com/writings/diary/archive/2020/0... [2] The SMILES string of molecule 69 from the paper, which is the one from the cryo EM structure: `C[C@@H]1C=C(c2c[nH]c3ncccc23)CNC1`
- cwkoss 4y agoThe article was written from the perspective of a 5HT2a receptor