I Like to Draw Pictures of Random Molecules

[Bagseed]

the discussion is about the diarylmethoxy carbon, not the tropan

 

[Solipsis]

You are right, but my point was: chirality is drawn if it is relevant, and at that stage of consideration it is only very generally shown that there are possible substitutions that are not necessarily equal but they may be equal or not present at all. There is nothing said of what they may be, so it seems irrelevant or premature to point out that there are potential chirality issues there. I think, like hydrogens it is not drawn until it really becomes a relevant matter. Anyway that's my take on it. Even if the chirality is not ambiguous anymore it is not necessarily drawn, unless it matters in the context. Look at the alpha carbon of amphetamines. Often enough ignored, cause it is not always significant in all matters.

 

[Pomzazed]

You are right, but my point was: chirality is drawn if it is relevant, and at that stage of consideration it is only very generally shown that there are possible substitutions that are not necessarily equal but they may be equal or not present at all. There is nothing said of what they may be, so it seems irrelevant or premature to point out that there are potential chirality issues there. I think, like hydrogens it is not drawn until it really becomes a relevant matter. Anyway that's my take on it. Even if the chirality is not ambiguous anymore it is not necessarily drawn, unless it matters in the context. Look at the alpha carbon of amphetamines. Often enough ignored, cause it is not always significant in all matters.

Sorry for introducing confusion. You are right that diphenylmethoxy- part is NOT chiral, due to having two identical (phenyl) group. It is just prochiral, The questions about chirality I asked is for in-case that the phenyls are asymmetrically substituted. (Eg, one Phenyl plus one chlorophenyl) from that jellyfish-like molecule

 

[sekio]

yes, then it'd be chiral because the quaternary carbon that bridges the two would have 4 differing substituents.

 

[Nagelfar]

Sorry for introducing confusion. You are right that diphenylmethoxy- part is NOT chiral, due to having two identical (phenyl) group. It is just prochiral, The questions about chirality I asked is for in-case that the phenyls are asymmetrically substituted. (Eg, one Phenyl plus one chlorophenyl) from that jellyfish-like molecule

yes, then it'd be chiral because the quaternary carbon that bridges the two would have 4 differing substituents.

I took it from "compound 276" from Singh's 1999 coke antagonist paper: i.e.

and the 12 series phenyltropane benztropine analogs, i.e.

-----------------

(1R,3R,5S)-8-methyl-3-(9-{naphtho[2,1-c]phenanthren-1-yl}phenanthren-3-yl)-8-azabicyclo[3.2.1]octane

^Again, can't draw it from the library again, but a mixture of all of the possible ligands by length of arene/aryl and phenyl/methylenes of the phenyltropane that have affinity. (maybe not together, LOL)

 

[Pomzazed]

The first one; cis-diphenylethene one may be light sensitive! It looks like some molecular probe that switch to trans when exposed to visible or IR, but revert to cis after shortwavelength UV lol :D

 

[roi]

May or may not have fentanyls-like potency

 

[DotChem]

MDMADMTDOB free base

 

[white55]

 

[Solipsis]

Oooh... I tried ETH-LAD last sunday so I can certainly appreciate this idea - how about the benzoyl amide though? That's said to be ridiculously long-lasting IIRC.

These 1-subbed lysergamides are a mystery: they shouldn't be active themselves and also don't seem to produce enough metabolite in time to really account for everything normally. LSD et al themselves seem really strange in that tiny quantities are necessary to successfully make it into parts of the brain to lodge themselves there.
So I think the question is: do these 1-subbed ones somehow favorably deliver enough those tissues - do the pro-drugs get stuck in the CNS' 5-HT2a and then get 1-deacylated making it virtually irrelevant what portion gets deacylated overall? I think what is suggested from the data is that as if the dosages aren't tiny already for LSD, what matters mostly is some even tinier dose that successfully gets lodged. Maybe that skews some perspective on what is needed to achieve that and maybe it is the source of confusion about 'not enough metabolite LSD being present to explain the potency of such pro-drugs'? Or was Nichols just wrong about the activity of these pro-drugs themselves or is it just that LSD dosage is so overstated when street acid is advertised?

Is 6-Cyclopropyl-LAD reactive / unstable? I think I remember only the cyclopropylmethyl in literature...

 

[sekio]

I'm pretty sure that the 1-alkyl LSD analogs are deacetylated rapidly in the blood and thereby act as prodrugs and nothing more.

 

[Bagseed]

But how come that the diethylamide isn't also cleaved enzymatically quickly to give lysergic acid?

 

[sekio]

The diethyl amide is more sterically hindered than the one on the indole nitrogen. Also, because the indole group is aromatic and that disrupts the conjugation of an amide group, the amide C-N bond on the indole is longer than the one "up top", rotates more easily, and is thereby more easily hydrolysed.

 

[Bagseed]

thanks

 

[adder]

This thread inspired me to draw a few 7-sulfonylbenzodiazepines. I'm pretty sure we know nothing about SAR that would make them inactive for some reason solely due to the sulfonyl group. The advantage is that unlike with halogens or nitro group, this group is not a dead end and can be modified with a variety of functional groups, aliphatic, cyclic, aromatic etc. which might be tuned to be selective for certain receptor subtypes.

 

[DotChem]

and replace it be a C.. you get this molecule: It is extremely potent NDMArA about 30x more potent than K as NMDAr antagonist (Ki 3HTCP binding = 27nM v Ket Ki = 860nm) according to this patent here. It doesn't look like any schedule dissociative at least the structure or can it be seen like ring restricted K analog or something?..but anyhow, it looks it might have an unbelievably long half life (>10 h???) considering there is no obvious "metabolizable" functional group to chew esaily by metabolic enzymes..But who knows?

 

[adder]

If -NHMe and -H at the junction between cyclohexane & indane rings are cis, it's quite like dizocilpine without the second aromatic ring.

 

[Solipsis]

:D so what was their plan with this 'treatment' for cerebrovascular disorders... administer it with a whopping dose of an equally long-lasting benzo?... mk-801 type trips seem a bit hardcore to give to a patient...

I will always be amazed at how the pharmacophore of NMDA antagonists seem to be based on NMDA but also not based on NMDA. Or from a different angle: how the PCP site would have evolved to apparently have similarities to the main active site with its pharmacophore, but also to develop what seems like a specialization so that there can exist an overlap in ligands active at both sites, but not necessarily. I guess the real PCP site ligands are more aromatic or even aliphatic etc rather than having polar groups like carboxyls. Anyway maybe I am off with this interpretation.. but suffice to say it has puzzled me

Someone should really build an LSTM network AI and feed it all known relevant data and get it to come up with novel drugs for us

wtf is this endogenous ligand's structure: https://www.ncbi.nlm.nih.gov/pubmed/2887250 for the PCP site?
Are all endogenous ligands in the brain basically 'designed' to not pass the BBB? I mean: are there endogenous brain neurotransmitters known that could be active when administered, is the BBB made to transport some compounds unilaterally or would you never find any such administerable drug because it would leak out of the brain if it could also get in there / or get metabolized really quickly before it could get anywhere?

 

[Nagelfar]

wtf is this endogenous ligand's structure: https://www.ncbi.nlm.nih.gov/pubmed/2887250 for the PCP site?
Are all endogenous ligands in the brain basically 'designed' to not pass the BBB? I mean: are there endogenous brain neurotransmitters known that could be active when administered, is the BBB made to transport some compounds unilaterally or would you never find any such administerable drug because it would leak out of the brain if it could also get in there / or get metabolized really quickly before it could get anywhere?

That paper was from 1987, and the PCP site is still considered an 'orphan receptor site' without adoption, last I knew. Was this paper disproven shortly thereafter perhaps?

 

[SkyblueMolly]

This is a molecule of N-Propargyl-Methiopropamine.
It's an analogue of deprenyl, an MAO-I.