| Autor: |
Grace, C. R. R., Durrer, L., Koerber, S. C., Erchegyi, J., Reubi, J. C., Rivier, J. E., Riek, R. |
| Zdroj: |
Journal of Medicinal Chemistry; January 2005, Vol. 48 Issue: 2 p523-533, 11p |
| Abstrakt: |
The three-dimensional NMR structures of six analogues of somatostatin (SRIF) are described. These analogues with the amino acid 4-(N-isopropyl)-aminomethylphenylalanine (IAmp) at position 9 exhibit potent and highly selective binding to human SRIF subtype 1 receptors (sst1). The conformations reveal that the backbones of these analogues have a hairpin-like structure similar to the sst2-subtype-selective analogues. This structure serves as a scaffold for retaining a unique arrangement of the side chains of d-Trp8, IAmp9, Phe7, and Phe11 or m-I-Tyr11 (m-I-Tyr = mono-iodo-tyrosine). The conformational preferences and results from biological analyses of these analogues1,2 allow a detailed study of the structure−activity relationship of SRIF. The proposed consensus pharmacophore of the sst1-selective analogues requires a unique set of distances between an indole/2-naphthyl ring, an IAmp side chain, and two aromatic rings. This motif is necessary and sufficient to explain the binding affinities of all of the analogues studied and is distinct from the existing models suggested for sst4 as well as sst2/sst5 selectivity. |
| Databáze: |
Supplemental Index |
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