Replacing the amine in phenethylamine

[TooMuch2C-E]

I tend to have a lot of time on my hands, the majority of which I spend reading up on organic chemistry, as well as various psychoactive substances. Recently I was reading up on tropane-based stimulants, and I came across an article about an analog of dichloropane in which the amine group in the tropane moiety is replaced by an oxygen ether link, demonstrating that the amine nitrogen is not necessary to yield psychoactive effects. This sparked my interest in reading up on analogs of substances I've already used and see how they differ in their effects (for example 2,5-dimethoxy-4-methylseleneophenethylamine in comparison to 2,5-dimethoxy,4-methylthiophenethylamine). I'm specifically interested in analogs in which an atom such as oxygen is replaced by a chemical of the same group. Now, bear in mind I'm a high school student, and the knowledge I possess I acquired by my own accord, so my comprehension isn't too advanced. Anyhow, my question is, if you were to replace the amine group in any phenethylamine analog with a phosphine group, would it still yield psychoactive effects? Or would that make it too distinct from catecholamines? Unfortunately, I don't think anyone's attempted to create phenethylphosphine to test this .

 

[nuke]

You generally want to have them (third row elements) somewhere where they won't be exposed to the active sites of any enzymes and are protected from reacting with by trisubstitution from alkyl groups. Otherwise there is a strong chance of irreversible inhibition due to these elements being more likely to form covalent bonds with residues on some protein. I believe monophosphenes are also not very stable and must be prepared under inert atmospheres, although someone more experience with organic/inorganic chem can probably elaborate on that.

 

[TooMuch2C-E]

It's nice to be posting somewhere that I can get straight answers. Much appreciated.

 

[Nexus298]

http://en.wikipedia.org/wiki/TOM_%28psychedelic%29
This shows where he substituted S for O and the results.

 

[tryp2fun]

The amine nitrogen in phenethylamines has a high pKa (ca. 10), so it is protonated at physiological pH, giving it a positive charge. This protonation seems important for binding to receptors. Monoalkylphosphines are weaker bases (pKa ~ 5), so they would be unprotonated at physiological pH. Furthermore, as mentioned above, monoalkyl phosphines are unstable in the presence of O2. Trialkyl phosphines are more stable and have higher pKas, but we know that trialkyl phenethylamines are weak binders at 5HT-2a receptors. Phosphines are also known to be rather toxic. So, it is unlikely that phenethylphosphines would be biologically active in an interesting way. Otherwise, I am sure that Shulgin would have looked at them.

 

[Hyperthesis]

Recently I was reading up on tropane-based stimulants, and I came across an article about an analog of dichloropane in which the amine group in the tropane moiety is replaced by an oxygen ether link, demonstrating that the amine nitrogen is not necessary to yield psychoactive effects.

This observation is called the "Grimm's Hydride Displacement Law", which states:

An atom, which is located up to 4 positions left of a noble gas, obtains upon addition of n = 1, 2, 3, 4 hydrogen atoms (some) properties of the elements, which are located n positions right of it.

Examples:
* A CH2-group can be replaced by a NH-group or by an ether-linker.
* A CH3-group can be replaced by a NH2-group or by a OH-group or a halogen.

This rule is a very general one and includes many exceptions. If only steric demand (and to some extend electronic properties, like lone electron pairs) is deciding for binding of a small molecule to a protein, then this rule applies comparably often.
If the charge is important (see tryp2fun's post!), or hydrogen-bridge forming properties, then the above rule usually fails.

I'm specifically interested in analogs in which an atom such as oxygen is replaced by a chemical of the same group.

This kind of bioisosteric replacement has nothing to do with the explain rule by Grimm, because you only exchange atoms within the same group of the periodic system of elements (PSE). In this case other rules apply:
First, remember that the size of the atoms increase the more you go down within one group in the PSE. This has implications for the sterical demand of a functionality within a molecule.
Second, the electronegativity changes in the same way (i.e. getting smaller the more you go down: O > S > Se > Te; Polonium is irrelevant for obvious reasons), which has implications for the overall electronic distribution of the molecule, which again has implications for e.g. the acid-base-properties, hydride bridge donor/acceptor properties and more.
Third, due to the explained change in electronegativity and size, the polarisability of an atom increases the more you go down in the PSE, which has some implications for the tendency to get attacked by a electrophilic species (in other words: the ease of e.g. alkalytion reactions at that atom).

Apart from the above rules, I'd like to add that selenium-analogs of most oxygen-functionalities show considerably higher toxicity for humans. This tendency is even more pronounced will tellurium. For this reason these elements are usually ruled out when it comes to compounds intended to be used in humans ... which leaves us with sulfur (see Nexus298's post for examples).

 

[Transform]

Don't let your interest wane. You sound like you have a lot of potential and your interest in chemistry outside the curriculum (as taboo as it may be) will motivate you well to become a talented scientist.

While the idea is a good one, it carries a few risks as others have pretty comprehensively covered.
Covalent bonding (therefore permanent) is usually very undesirable in pharmacology, sulphur is much more prone to this than oxygen.
Phosphines are pretty unpleasant, and for the most part I'd be unhappy testing them on myself. Toxicity of many things increases as you move down the periodic table, for many reasons, and the p-block shows some pretty good examples of this, so many of these compounds are pretty uninvestigated.

 

[23536]

fish produce a modified form of glycine

I guess this would be an arseno acid?

 

[reformer]

need nitrogen for a salty interaction, yaaargh!

Anyhow, my question is, if you were to replace the amine group in any phenethylamine analog with a XXX group, would it still yield psychoactive effects? .

I think Tryp2fun nailed it with their explanation via pKa... since the nitrogen is the only element that springs to mind as carrying a positive charge under physiological pH, it's unlikely you'll find an apt replacement for the amine group.

Can anyone think of a suitable element to replace nitrogen? Since PEAs carrying N-alkylation seem to lose potency, that would seem to rule out using trialkylsulfonium or trialkylselenonium to carry a constitutive charge in place of the nitrogen. Any others?

Regardless, this figure taken from Braden's Dissertation explains the essentiality of the nitrogen atom with a glance. I highlighted the ammonium/carboxylate salt pair in green, of which the nitrogen atom forms half and aspartate 155 from the h5HT2a serotonin receptor forms the other half.

 

[negrogesic]

Certainly something explore......but i'd avoid self-testing here.....there are some unknowns here and i'm thinking toxicity......

 

[Hyperthesis]

It is known that going from the primary to the secondary resp. tertiary amine (i.e. increasing sterical demand) abolishes activity of the PEAs. Because there is no other element resp. functional group which can be charged positively AND remain the small size of a nitrogen-atom, it will be hard if not impossible to find an active replacement for the N in PEAs.

 

[specialspack]

Braden's Dissertation

Sorry, what's this?

 

[Astavats]

Spack it's M.R. Braden's 'Towards a biophysical understanding of hallucinogen action'