Fertile
Bluelighter
- Joined
- Mar 31, 2022
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The compounds in European Patent EP1055665B1 '3-(3-Hydroxyphenyl)-3-amino-propionamide derivatives' are discussed in the article
'Design, synthesis and biological evaluation of 3-amino-3-phenylpropionamide derivatives as novel mu opioid receptor ligands.'
Allen MP1, Blake JF, Bryce DK, Haggan ME, Liras S, McLean S, Segelstein BE
Bioorganic & Medicinal Chemistry Letters, 01 Mar 2000, 10(6):523-526
DOI: 10.1016/s0960-894x(00)00034-2
Now the paper shows that a m-OH on the A aromatic is required for significant affinity BUT phenolic compounds all behave as antagonists. The examples are also mainly secondary amines BUT if one removes the meta-OH, adds a para-Br and makes the amine tertiary (dimethyl), the resulting compound (with 2 carbons between amide & B aromatic) overlays BDPC exactly. Not nearly, but exactly.
When I say that, I mean that the lone-pairs of the amine and the O overlay. The =O of the amide is slightly closer to the A aromatic than the -OH of BDPC but the lone-pairs (the items relevant to affinity) are in the correct spatial positions.
I should add that I looked into other opioids with their amine connected to the benzylic carbon and in all cases (ciramadol, doxpicomine, trimebutine) are all (R). That last detail does not seem to have been recognised but their is still no firm rules about what makes an opioid. For any rule their will be exceptions.
I can only read paper on-line but if someone can upload it so everyone can read, that would be most useful. If we have 2 scaffolds that follow to positions of the 4 key moieties of BDPC it may be possible to design totally novel ones.
'Design, synthesis and biological evaluation of 3-amino-3-phenylpropionamide derivatives as novel mu opioid receptor ligands.'
Allen MP1, Blake JF, Bryce DK, Haggan ME, Liras S, McLean S, Segelstein BE
Bioorganic & Medicinal Chemistry Letters, 01 Mar 2000, 10(6):523-526
DOI: 10.1016/s0960-894x(00)00034-2
Now the paper shows that a m-OH on the A aromatic is required for significant affinity BUT phenolic compounds all behave as antagonists. The examples are also mainly secondary amines BUT if one removes the meta-OH, adds a para-Br and makes the amine tertiary (dimethyl), the resulting compound (with 2 carbons between amide & B aromatic) overlays BDPC exactly. Not nearly, but exactly.
When I say that, I mean that the lone-pairs of the amine and the O overlay. The =O of the amide is slightly closer to the A aromatic than the -OH of BDPC but the lone-pairs (the items relevant to affinity) are in the correct spatial positions.
I should add that I looked into other opioids with their amine connected to the benzylic carbon and in all cases (ciramadol, doxpicomine, trimebutine) are all (R). That last detail does not seem to have been recognised but their is still no firm rules about what makes an opioid. For any rule their will be exceptions.
I can only read paper on-line but if someone can upload it so everyone can read, that would be most useful. If we have 2 scaffolds that follow to positions of the 4 key moieties of BDPC it may be possible to design totally novel ones.