Development of a model for the δ-opioid receptor pharmacophore. 4. Residue 3 dehydrophenylalanine analogues of Tyr-c[D-Cys-Phe-D-Pen]OH (JOM-13) confirm required gauche orientation of aromatic side chain
✍ Scribed by Henry I. Mosberg; Rajesh K. Dua; Irina D. Pogozheva; Andrei L. Lomize
- Publisher
- Wiley (John Wiley & Sons)
- Year
- 1998
- Tongue
- English
- Weight
- 758 KB
- Volume
- 39
- Category
- Article
- ISSN
- 0006-3525
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✦ Synopsis
We have previously proposed a model for the 6-opioid receptor binding conformation of the high afinity tetrapeptide Tyr-c[D-Cys-Phe-D-Pen] OH (JOM-13) based on experimental and theoretical conformational analysis of lhis peptide and a correlation of conformational preferences of further conformationally restricted analogues ofthis tetrapeptide with their receptor binding afinities. A key element of this model is the requirement that the Phe3 side chain exist in the X I = -60" conformation. Conformational calculations on the residue 3 dehydrophenylalanine analogues of JOM-13 suggest that while the dehydro(Z)phenylalanine analogue can be superimposed easily with the proposed binding conformer of JOM-13, the dehydro-(E)phenylalanine analogue cannot. These results lead to the prediction that the dehydro(Z)phenylalanine analogue should display similar &receptor binding ajinity as JOM-13 while the dehydro( E)phenylalanine analogue is expected to bind less avidly. Synthesis and subsequent opioid receptor binding analysis ofthe dehydrophenylalanine analogues of JOM-13 confirm these predictions, lending support to the 6-pharmacophore model. 0 I996 John Wiley & Sons, Inc.