N-benzyl phenethylamines

[Bondmaker]

Might be a moot point, but...

Isn't 2-methoxybenzyl a useful protecting group for primary and secondary amines because it's sterically hindered and imparts a partial positive charge(+R resonance effect) on the carbon ortho to the carbon that's attached to the ortho methoxy group, by resonance (rather than -I, inductive electron pull by the oxygen). This pulls electron density away from the benzylic carbon which in turn makes the amine less basic , and thus more susceptible to hydrogenolysis?
I don't know what a less basic nitrogen atom would do for psychedelic effects (as far as receptor recognition is concerned), so it must be a total molecule effect on the receptor recognition and the molecules activity. If the para methoxy compond were as potent, this might add to some support for the weakening of the basic nitrogen's effect on psychedelic effect?
Am i totally off base here?

 

[fastandbulbous]

If the amine is less basic, it might reduce the affinity for the receptor as the sidechain nitrogen of PEAs & tryptamines as well as the D-ring heterocyclic nitrogen have an important role in hydrigen bonding to an aspartate residue in one of the transmembrane chains of the receptor protein.

All pure speculation though

 

[Bondmaker]

is it not true that...

Addition of an electron releasing alkyl moiety (methyl group, makes the nitrogen more basic) on MDA attenuates it's paychedelic action (resulting in it being called more an "empathogen") and thus one doesn't get the "swirling colors" and "trippy traces" that one gets with unsubstituted MDA (a definite "psychedelic)? Also, most unsubstituted trptamines are inactive (acylated tryptamines like melatonin being totally inactive as a psychedelic, but an amide is a totally different creature than an amine anyway). And tryptamine itself is only active when dimethylated (active when smoked), or diethylated (oral activity). Is this like dopamine, no BBB penetration?
MY point here is in an amphetamine series, it appears that a less basic nitrogen, here the primary amines (structural aspects ignored) gives an enhanced potency and general stimulant effects, whereas in MDA and methamphetamine (both N-methyl substituted and thus having more basic nitrogens) are "smoother" but lower in potency to see noticeable effects.
THis post is a bit convoluted, but i'm wondering if someone could tell me anything more about receptor recognition in these compounds. What i've gotten so far from a several of you is that amphetamines and tryptamines act by binding to receptor reuptake (DA, 5-HT, NE) sites presynaptically leading to flooding of the cytosol between neaurons with the endogenous ligands, and not so much as postsynaptic binding mimetics of the endogenous ligands. This being true would be an efffective arguement for the down regulation that we see in the neuronal activities, with these compounds.
All that being said, there must be specific sites on the presynaptic neuron where these compounds bind to block reuptake. Since activity is determined by the "on-off" time of the compound at the receptor site, has a general, predictable SAR been developed that brings together both compound structure and conformation, and nitrogen basicity at the various reuptake blocking sites, thus shedding light on the amino acid sequences of these receptor sites. They must be transmembrane proteins and thus difficult to elucidate. Fastandbulbous eluded to something being known about the receptor sites active pocket, but how much is really known about the various receptor geometries?
Is this a reasonable set of questions, or am I in waters unknown here?

 

[MattPsy]

Either you posted in the wrong thread or you've got confused somewhere along the line (in regards to the comments about reuptake and stuff).

Psychedelic phenethylamine and tryptamine derivatives act by binding to and inducing a specific comformational change in the serotonin 2A receptor. It's true that a small variety of them have other actions (we're talking AMT, AET, MDA, etc here), but that's because of the similarities in the required binding motifs (ie a alkoxy subbed benzene ring in some).

Psychedelic PEAs and tryptamines have their own SARs, as you've noted. There have been attempts to explain this, for example F&B's acid & dragonflies thread here on BL (search for it, it's a good thread).

The interesting thing with these N-benzyl ones is that they appear to be binding to the same other Phe residue that LSD does. When that region of the coding for the receptor was mutated, DOI and friends didn't suffer much loss in activity (because they aren't interacting with it, likely), but LSD and these N-benzyl ones weren't nearly as well off - it ruined their activity.

 

[dorothyperkins]

The interesting thing with these N-benzyl ones is that they appear to be binding to the same other Phe residue that LSD does. When that region of the coding for the receptor was mutated, DOI and friends didn't suffer much loss in activity (because they aren't interacting with it, likely), but LSD and these N-benzyl ones weren't nearly as well off - it ruined their activity.

Oh really!

 

[Smyth]

The proof of the pudding...

Do you think any human has tried these compounds yet?

5-HT2A antagonists are being marshalled as potential antidepressants and treatment agents for psychostimulant abuse.

However, 5-HT2A agonists are believed to disinhibit dopaminergic neurotransmission along pathways originating from the ventral tegmental area (VTA), including the nucleus accumbens (NAc).

Beyond the obvious safety and ethical implications of novel analogs, im wondering for compounds displaying such encouraging in vitro data, whether anybody has considered testing these yet?

I was shocked and surprised when bromo-dragonfly made it onto the RC marketplace, so all im saying by this is that stranger things have happened.

 

[dorothyperkins]

Not that i know of. Will require care since they could be more potent than lsd or totally inactive!

 

[fastandbulbous]

Fastandbulbous eluded to something being known about the receptor sites active pocket, but how much is really known about the various receptor geometries?
Is this a reasonable set of questions, or am I in waters unknown here?

Bondmaker, there's some info on the binding site in the thread,'Acid, dragonflies & the 5HT2a receptor' - It's a long meandering sprawl I wrote about the SAR of serotonogic psychedelics, mainly focusing on the common structural/stereochemistry features of LSD, tryptamines & phenethylamines. There are a couple of diagrams relating to the amino acid residues that different parts of the drug molecule interact with.

PS You'll need to search as I'm having a more lazy than usual day, even though it would be shameless self promotion (which I've been known to partake in occasionally! )

 

[LuxEtVeritas]

^ there is no shame in pimpin a well respected related thread that one has largely "authored"...the travesty would be if one did not point those who would have interest in the right direction regardless %)