I know about guanidines, or nitrogen-containing heterocycles acting as bioisosteres of amines in different contexts.
I also know about the -OH, -NH2, -SH isosterism, which is rather poor and does not replicate the basic/acid properties.
So I wonder, if any metaloids or their isotopes could behave as a basic nitrogen, and therefore as a potential bioisostere that could fit in neurotransmitter analogues.
Hi there!
If you're trying to find bioisosteres for -NH3+, I can think up a few possibilities. The first that comes to mind is to fluoronate it to -NF3+, which would preserve the cationic quaternary amine N (without the associated acid/base chemistry). Of course, if you want hydrogen, I suppose you could try only mono/difluronating the amine. Na+ is fairly similar to the ammonium cation, but probably not useful for your purposes.
I can't speak towards whether or not the bioisostere will fit in NT analogues; perhaps you can give me more information about the molecule that you're trying to modify and the effect you're interested in mimicking within in. Is it merely the positive charge? You mentioned "with or without" hydrogen. Would a purely steric substitution (e.g. -N(CH3)3 to a t-butyl) work for your purposes as well?
Edit: yes, a phosphonium substitution sounds like a valid choice as well.
Thanks a lot for your response Joseph, I didn't know about -NF3+, I'll look into that.
I am interested in mimmicking alkyl-amines (primary, secondary or tertiary) with short substituents no longer than ethyl. Alkyl-ammonium isalso welcome. Basically, the moieties that are generally known to bind to aromatic-NT receptors and efficiently activate them.
My pleasure, Mario. F is a common isostere for H, which is what made me think of it first.
I see--so something that would bind happily with aspartate, I imagine. The positive charge is more important than the presence of hydrogen. You mentioned phosphonium; what about a methylated sulfonium (-S(CH3)2+)?
Vladimir's comment made me reconsider the fluoronated nitrogen, so I looked into it. Turns out, the bond is pretty unstable. It's doable on an industrial level, but probably not practical for your purposes. I'd stick with a phosphonium or sulfonium substitution. Those will be far easier to work with.
N-F containing reagents are generally fluorinating compounds. I don't think these would be stable in a biological system and might even be highly toxic due to the release of HF.
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