(±)-McN 5652

[clubcard]

US 4908450 'Certain hexahydro-6-arylpyrrolo[2,1-A]isoquinolines'
US 4595688 'Hexahydropyrrolo[2,1-a]isoquinoline derivatives and antidepressant use thereof'

People will notice that the above are a development of:

US Patent 3947456 'Substituted 4-Phenyl Isoquinolines'

Themselves developed from and related i.e. poperidine ring swapped for morpholine ring or thiomorpholine ring.

US Patent 2820038 - 2-Diphenyl-Methyl-Piperidine

Which are simple ring-expansions of.

https://doi.org/10.1021/ja01100a043

Taking us all the way back to:

AMPHETAMINES

 

[Rectify]

You seem super smart, but this thread would make a lot more sense with Kekule structures. :/

 

[Nagelfar]

…this thread would make a lot more sense with Kekule structures. :/

Philosophical theories of 'windowless monads' rush to the forefront of my mind.

That we all only see our private worlds, enriched only by the criteria whereby we give over to a particular fetishism.

Rorschach tests and stereograms; all manner of reading into things based on preconceived notions that extend no further than our own fancy. Limited to our most familiar medium as it conveys importance to our senses.

The structure itself, being the most vague aspect regarding what it can induce, the most abstract part of it's mechanism of action that is wholly dependant on the environment outside itself.

I too, need assistance in imagining a purported molecule's nature, and hope also to become as knowledgeable by verbal description and naming convention to it's potential as any other way, moreso even, than being limited by just one among many possible designs one could give by a more encompassing nomenclature.

Molecular image structuring has become an arcane pass time here, but we can broaden our horizons further. So much education to be had.

 

[Rectify]

That sounds poetic.

 

[Nagelfar]

↑That "rectify" the situation? ;-p

Opening up that patent nearly crashed my phone. I skimmed it, skipping numerous example images, and only got three quarters of the way through before accidentally closing the tab. Didn't want to try opening it again.

(of course, I did anyway, not that bad it's just this day and age anything that hangs for over a minute feels like it isn't loading properly)

They look like those restricted rotational analogs of methylphenidate with various amendments.

 

[Rectify]

Exhaustive!

 

[clubcard]

JNJ-7925476 (6-(4-Ethynyl-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

US-2012190725-A1	Inhibitor(s) of transporters or uptake of monoaminergic neurotransmitters	2009-07-23
US-8772330-B2	Inhibitor(s) of transporters or uptake of monoaminergic neurotransmitters	2009-07-23	2014-07-08
WO-2011011277-A1

So, we have data on the p-SCH3 and now the p-ethynyl which appears to be a triple reuptake inhibitors. I haven't been able to find an ED50 or Ki (I know it's sub nM) at the various transports BUT I suspect most of the 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline class will be long-acting. As I have mentioned, a p-methyl in place of the p-ethynyl or p-thiomethyl would result in something along the lines of MDMA but needing a much lower dose. That p-Me will be a great target for the body to oxidise to the aldehyde and then the carboxylic acid which will be removed mostly as the sodium salt.

The KEY thing is that the pyrrolo ring moves the N: slightly i.e. the drug binds to the transports far more readily.

While the '3'4'-dichloro analogue is known, It would be fascinating to learn what a m-OCH3 would be like....

Too much work but imagine an MDMA-like with the potency of LSD. That would turn the industry on it's head.

 

[Nagelfar]

I wonder how the para–ethynyl SNDRI would compare to phenyltropanes?

 

[vecktor]

These all could be called the descendents of nomifensine and diclofensine so are primarily reuptake inhibitors rather than monoamine releasers like MDMA. Hoffmann la Roche and Hoechst had already got most of the patent space so these are me too compounds from McNeil now part of J&J.
A couple of the simpler tricyclic compounds are potent DRIs but with unfortunate toxicology.

 

[clubcard]

It would certainly be interesting to see what (if any) effects the addition of an aromatic 8-NH2 as seen in the nomifensine structure. While I know that aromatic -NH2 moieties can be bad news, if the active dose is 2 or 3 orders lower then the toxicity MAY not become an issue. That -NH2 has interested me since diclofensine lacks it BUT has an unexpected -OCH3...

But the point I was making was that it's easy to see that the position & direction of the N: has seemingly been optimised.

I have read reports on the subjective effects of nomifensine and it certainly sounded positive.