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    Simplest molecule filling morphine rule? 
    #1
    Bluelighter dread's Avatar
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    I got bored and started thinking, what would be the absolutely simplest molecule to fulfill the morphine rule?

    It doesn't have to be an existing / already synthetized substance, or active substance. I'd just like to know, purely out of curiosity, what would be the simplest possible substance still fullfilling the rule?

    I'm pretty sure most in here know the morphine rule, but here's a reminder:
    - has tertiary amine
    - has quarternary carbon
    - aromatic ring connected to quart. carbon
    - 2 carbon chain between tert. amine & quart. carbon
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    #2
    Well, quite obviously, it would be N,N,3-trimethyl-3-phenylbutan-1-amine - which is the morphine rule personified, so to speak. That's what you get when you take a tertiary amine connect a 2 carbon spacer, a carbon to that and then add two methyls and a phenyl group on that last carbon. Not counting for double bonds, though.

    It's a known substance, even has it's own number, LS-47438

    It was reported in Journal of Medicinal Chemistry. Vol. 11, Pg. 340, 1968- which I do not have (hint hint murphy! ), though I have no clue what they were looking at. I'm assuming it was part of the search for methadone analogues.
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    #3
    Bluelighter immaturepoop's Avatar
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    I don't know how to import ACD chemsketch images, but here is a pic of what N,N,3-trimethyl-3-phenylbutan-1-amine looks like:

    http://www.personal.kent.edu/~cearle...rphinerule.gif

    this is for those who seem to do better with pictures like me! haha
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    #4


    I use ChemBioDraw and LOVE it. I even use it for note taking when I'm researching something. By the end I've got ten pages open full of notes and diagrams and when I'm done, it's easy to copy them into ChemBio3D or save them as individual images, etc.
    Last edited by Hammilton; 24-11-2008 at 06:39. Reason: doesn't like my gif's for some stupid reason...
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    #5
    Bluelighter immaturepoop's Avatar
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    Not to stray too off topic but thanks! I'll look into ChemBioDraw. And your picture isn't showing up for me...

    edit: ok there it is! :-)
    Last edited by immaturepoop; 24-11-2008 at 07:11. Reason: and now i see!
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    #6
    Me either, wtf.. I'll try another host.

    The host was the problem. Why can't we link from ImageShack? Anti drug or something?
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    #7
    Bluelighter dread's Avatar
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    Yeah but if we count all the hydrogens too... What would be the Absolutely simplest, least atoms containing molecule? I'd think if you made that chain cyclic there would be at least 2 less hydrogens...

    Also the morphine rule only states "aromatic ring", it doesn't say it has to be phenyl?
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    #8
    Bluelighter dread's Avatar
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    I was thinking of something like this:

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    #9
    Also the morphine rule only states "aromatic ring", it doesn't say it has to be phenyl?
    Actually it says, at least originally, "phenyl or isoteric equivalent."

    Some other aromatics work, like thiophene, at least in some circumstances, probably not all.
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    #10
    Okay, I have the paper now, thanks to Murphy. The drawn molecule is active, though pretty weak.

    Compound_______Hot Plate_______Writhing_______Yeast Inflamm._______LD50 (mg/kg)

    Codeine _______50po___________ 22.8po________ 40po________________212
    V _____________<200po_________76 po_________>200po______________152
    XIII ___________>20Opo/33sc ____38.5po________>200po______________210

    V = N,N,3-Trimethyl-3-phenylbutylamine
    XIII = 3-(3-hydroxyphenyl)-3,N,N-trimethylbutylamine
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    #11
    Bluelighter dread's Avatar
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    Do you think 3-{2-[2-(dimethylamino)ethyl]morpholin-2-yl}phenol would be active?
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    #12
    The molecule described provides enough "molecular geometry" to be turned into 4-phenyl quinuclidine (some hydrogens are lost from the creation of cylic portions). I don't know if this would be considered "simpler", due to its slightly lower molecular weight, or more complex due to its geometry. Evidently, the pharmacological action of the 4-phenyl quinuclidine derivates more resembles nerve gas than an opioid, so interest in a "cleaner agonist" kinda evaporated at that point. I'd like to research the LS-47438 molecule, but with a furan group attached in place of the benzene. I'm sure that such a molecule has been synthesized, but I can't find references to it online. I'm ALSO not sure of how to name the darned thing. Any ideas?
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    #13
    are you saying that the the molecule I drew could become 4-phenyl quinuclidine when ingested? I don't think that's plausible. The mice seemed to handle it find.

    molecular weight isn't altered much, 191.31 vs. 187.28, but the same number of carbons (just four fewer hydrogens). In terms of chemistry involved, it certainly becomes a lot more complex. And at least we know that N,N,3-Trimethyl-3-phenylbutylamine (and the m-hydroxy variant) are active and won't kill you...
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    #14
    Bluelight Crew fastandbulbous's Avatar
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    ^ No we know it's active in rats and that said dose will not kill them, humans are distinctly different creatures
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    #15
    HAMMILTON, I shoulda found a better way of putting it. I don't think the LS-47438 molecule would be converted to 4-phenylquinuclidine, and didn't mean to sound like I thought it would. I was playing around with a molecular modelling kit once upon a time and found that the LS-47438 molecule could be twisted into the 4-phenylquinuclidine molecule (minus some hydrogens). My literature search on this latter molecule revealed an extremely low therapeutic index(or that's the way I remember reading it, reaching back 20 years).
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    #16
    I gotcha now.

    ^ No we know it's active in rats and that said dose will not kill them, humans are distinctly different creatures
    I think it's safe to say it's active in humans, as well. Safety wise, though, it's hard to say. Related compounds aren't toxic at first glance, though.
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    #17
    Thought tapentadol would be the simplest mU agonist molecule, following the prototype rules.
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    #18
    This is best confirmed with someone who has more letters at the end of their name than me, but the notion of therapeutic index might be instructive. I think one WORKING definition of it might be LD(50)/ED(50). I'm assuming for this exercise that the EDs are actually in mg/kg. If we use the dose-response info that Hammilton provided for the 3 agonists, Codeine, LS-47438, and 3-(3-hydroxyphenyl)-N,N,3-trimethylbutan-1-amine, it gets interesting fast.
    The tail-flick, writhing and yeast inflammation doses are averaged. For the ones using > or < notation, let's use the actual numbers. "ED(50)" for the three agonists are, respectively, 37.6mg(let's call it 40 mg), 159mg, and 146mg. LD(50)s run 212mg/kg, 152mg/kg, and 210mg/kg. Codeine has a therapeutic index of 5.3. LS-47438 has 0.96, and the 3-hydroxy variant has 1.46. Evidently, getting simpler means getting more toxic. Must be all sorts of "pharmacodynamic forgiveness" in that phenanthrene molecule.....darn it.....
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    #19
    Hey HAMMILTON, instead of a trimethylamine group on the LS-47438 molecule, imagine it with a piperidine group. How would you name that?
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    #20
    Bluelight Crew Beenhead's Avatar
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    Quote Originally Posted by Hammilton View Post


    I use ChemBioDraw and LOVE it. I even use it for note taking when I'm researching something. By the end I've got ten pages open full of notes and diagrams and when I'm done, it's easy to copy them into ChemBio3D or save them as individual images, etc.
    I write all my papers with Chembiodraw, and 3d. I even have Merck INdex on ChemFinder!

    It makes my papers look soo bad ass
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    #21
    Um... well, it has a dimethyl group, which is what I assume you meant to say, and it'd be 1-(3-methyl-3-phenylbutyl)piperidine, which is sort of obvious, I think.
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    #22
    Bluelighter dread's Avatar
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    What if you'd replace one of the methyls on the amine with a phenethyl group?
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    #23
    No matter how often I study it, nomenclature is never obvious to me. It appears that the most basic morphine rule filling molecule isn't ENTIRELY bereft of applications. It's a substructure for an antidepressant known as nafenadone. Not exactly what I'd HOPED out of the molecule, but edifying, nonetheless.
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    #24
    Has anyone taken a good hard look at the milnacipran (Savella) structure? By itself, it doesn't fit the morphine rule. But if someone decided to methylate the primary amine to a tertiary amine, all morphine rule constraints are satisfied. If the carbonyl group survives the di-amination reaction, the end result can be found at PubChem or ChemSpider, but precious little is said of its pharmacodynamics. Thoughts, anyone?
    BTW, the reason you're not seeing a structural formula for both molecules is that I don't know how to put them on here.
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    #25
    Bluelighter dread's Avatar
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    This is milnacipran... Somehow I have a feeling that if you dialkylated that primary amine you would end up with an antagonist or partial agonist...
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