As viewers will notice, every example contains an amide moiety i.e. a non-basic nitrogen. Amides are also found in barbs, ludes, benzos and almost every class of sedative hypnotic.
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Downers - Amides with everything
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As viewers will notice, every example contains an amide moiety i.e. a non-basic nitrogen. Amides are also found in barbs, ludes, benzos and almost every class of sedative hypnotic.
It's ALMOST the case that their are amide & non-amide downers, Non-amide downers in effect act like inhalational anesthetics. They tend to be toxic, lead to a hangover and are toxic in overdose. About the only example that straddles that boarder is clomethiazole (and bromethiazole). These latter compounds are not well explored. We KNOW that they are very toxic if mixed with alcohol but they bind at a novel site. Not the benzodiazepine site, not the barbiturate site bur not more generally as per the manner of the non-selective agents that act more like sevoflurane than any decent hypnotic.
I have looked and looked but because clomethiazole was discovered in 1931, retrospect occurred in the 1950s, a period in which we still did not have a good handle on such agewnts.
What I CAN tell you is that all of the agents I picture induce CYP2D6 and so when taken with codeine, dihydrocodeine, hydrocodone, oxycodone and tramadol undergo O-demethylation and thus are much stronger. I don't think doctors caught on until the 1970s when they were all abruptly BANNED.
Oh, their IS ONE exception:
The above was commonly used in the UK until the mid 1980s when modern alternatives like diazepam, nitrazepam and temazepam became commonplace. I have no other homologues to compare it with so HOW it binds I really do not know.... but if YOU know, pleas post. It's simple to make and finding some interesting analogues would pose a real challange.
I have looked and looked but because clomethiazole was discovered in 1931, retrospect occurred in the 1950s, a period in which we still did not have a good handle on such agewnts.
What I CAN tell you is that all of the agents I picture induce CYP2D6 and so when taken with codeine, dihydrocodeine, hydrocodone, oxycodone and tramadol undergo O-demethylation and thus are much stronger. I don't think doctors caught on until the 1970s when they were all abruptly BANNED.
Oh, their IS ONE exception:
The above was commonly used in the UK until the mid 1980s when modern alternatives like diazepam, nitrazepam and temazepam became commonplace. I have no other homologues to compare it with so HOW it binds I really do not know.... but if YOU know, pleas post. It's simple to make and finding some interesting analogues would pose a real challange.
Ah - deliberate mistake in top image - should be C=O bonds, not C=C bonds.
But if you investigate further, from benzos to barbs to urea derivatives - all amides.
I am, however, convinced that the above compounds will O-demethylate codeine, tramadol, hydrocodone & oxycodone (plus any prodrugs that have an aryl-methyl ether.
But if you investigate further, from benzos to barbs to urea derivatives - all amides.
I am, however, convinced that the above compounds will O-demethylate codeine, tramadol, hydrocodone & oxycodone (plus any prodrugs that have an aryl-methyl ether.
Nobody does - it's a total mystery. 4-aminoglutethimide is also in inducer.... but that is a drug for cancer. If you find the other inducers, you will see there is no pattern. Pyrithylsione is supposed to be an inducer, but not as potent as glutethimide or such.
purplehaze147
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Edit: none of those classes you named contain amides R-CNO-R,R (as seen in LSD) or amino R-N-R,R (as seen in amphetamine) groups.
Piperidione and pyrithyldione don't contain amino groups in the example you gave. Neurosteroids are another whole group of GABAA allosteric modulators. Tert-amyl alcohol feels like it's nearly a selective GABAA PAM.
Our endogenous allosteric modulators of the GABAA receptors lack amino groups - these are neurosteroids and inosine (inosine has plenty of nitrogens but no amino groups).
Piperidione and pyrithyldione don't contain amino groups in the example you gave. Neurosteroids are another whole group of GABAA allosteric modulators. Tert-amyl alcohol feels like it's nearly a selective GABAA PAM.
Our endogenous allosteric modulators of the GABAA receptors lack amino groups - these are neurosteroids and inosine (inosine has plenty of nitrogens but no amino groups).
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I did state from the outset that AMLOST all downers contain an amide moiety. I could draw up a list of tens of thousands of examples to back that up. I think anyone with a basic grasp of medicinal chemistry will understand that uterides are bioisosteres of amides. After all, one could argue that alprazolam does not contain any amides.... It has an imine and a triazole ring, but electronically, the ring is acting as the bioisostere of an amide. I would hardly have used them as examples otherwise.
In the case of LSD, it's telling that the amide function can be swapped for an aromatic ring with an ortho methoxy moiety, for example. From that we can deduce that it's the receptor interactions are mediated by the
and the steric bulk of the group, 5 membered aromatics with an oxygen at the 2 position were produced to really understand that specific case. Nichol's team really spend an age on that one.
Better to examine it's electronic structure, not it's IUPAC. The inductive and conjugative effects & often steric bulk are what is important to bioactivity.
In the case of LSD, it's telling that the amide function can be swapped for an aromatic ring with an ortho methoxy moiety, for example. From that we can deduce that it's the receptor interactions are mediated by the
and the steric bulk of the group, 5 membered aromatics with an oxygen at the 2 position were produced to really understand that specific case. Nichol's team really spend an age on that one.Better to examine it's electronic structure, not it's IUPAC. The inductive and conjugative effects & often steric bulk are what is important to bioactivity.