Please delete this if it's frivolous.
I think that the 1-position on the indole ring corresponds to the amine on phenethylamine 5ht agonists. It always puzzled me that the N-dimethyl derivatives of phenethylamines and phenylisopropylamines show no activity, but then I remembered an article (I can't at the moment remember the title) that briefly mentioned benzofuran analogues of tryptamines, indicated that the 1-hydrogen on the indole seemed to be an important part of the binding process; the benzofuran analogues tend to around 1/5 the activity of indoles. MLD41 for instance shows greatly decreased and delayed activity and it is hypothesised that the activity it does show is the result of in vitro metabolisation to lsd.
Now this is scanty evidence, sure, but it's somewhere to start.
So I drew up the map of the overlapping rings, which looked good. The hydrophobic/philic zones seemed to match up fairly well. Various novel structures, based on this superposed image, jump out at one that may be found to be potent 5HT agonists. One in particular looked most obvious, the lactam version of 2c-g-4 smiles: CCN1CC2=C(CC1=O)C(OC)=C(CCN)C=C2OC but it would be rather a bitch to put together.
N-vinyl (or N-propargyl?) compounds would be one of the simplest evidences of this hypothesis; however I have found no precedent for them in the literature.
I think that the 1-position on the indole ring corresponds to the amine on phenethylamine 5ht agonists. It always puzzled me that the N-dimethyl derivatives of phenethylamines and phenylisopropylamines show no activity, but then I remembered an article (I can't at the moment remember the title) that briefly mentioned benzofuran analogues of tryptamines, indicated that the 1-hydrogen on the indole seemed to be an important part of the binding process; the benzofuran analogues tend to around 1/5 the activity of indoles. MLD41 for instance shows greatly decreased and delayed activity and it is hypothesised that the activity it does show is the result of in vitro metabolisation to lsd.
Now this is scanty evidence, sure, but it's somewhere to start.
So I drew up the map of the overlapping rings, which looked good. The hydrophobic/philic zones seemed to match up fairly well. Various novel structures, based on this superposed image, jump out at one that may be found to be potent 5HT agonists. One in particular looked most obvious, the lactam version of 2c-g-4 smiles: CCN1CC2=C(CC1=O)C(OC)=C(CCN)C=C2OC but it would be rather a bitch to put together.
N-vinyl (or N-propargyl?) compounds would be one of the simplest evidences of this hypothesis; however I have found no precedent for them in the literature.