Novel sst2-Selective Somatostatin Agonists. Three-Dimensional Consensus Structure by NMR
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- 作者：Christy Rani R. Grace ; Judit Erchegyi ; Steven C. Koerber ; Jean Claude Reubi ; Jean Rivier ; and ; Roland Riek
- 刊名：Journal of Medicinal Chemistry
- 出版年：2006
- 出版时间：July 27, 2006
- 年：2006
- 卷：49
- 期：15
- 页码：4487 - 4496
- 全文大小：560K
- 年卷期：v.49,no.15(July 27, 2006)
- ISSN：1520-4804
文摘
The 3D NMR structures of six octapeptide agonist analogues of somatostatin (SRIF) in the free form aredescribed. These analogues, with the basic sequence H-DPhe/Phe2-c[Cys3-Xxx7-DTrp8-Lys9-Thr10-Cys14]-Thr-NH2 (the numbering refers to the position in native SRIF), with Xxx7 being Ala/Aph, exhibit potentand highly selective binding to human SRIF type 2 (sst2) receptors. The backbone of these sst2-selectiveanalogues have the usual type-II' 
-turn reported in the literature for sst2/3/5-subtype-selective analogues.Correlating the biological results and NMR studies led to the identification of the side chains of DPhe2,DTrp8, and Lys9 as the necessary components of the sst2 pharmacophore. This is the first study to show thatthe aromatic ring at position 7 (Phe7) is not critical for sst2 binding and that it plays an important role in sst3and sst5 binding. This pharmacophore is, therefore, different from that proposed by others for sst2/3/5 analogues.
-turn reported in the literature for sst2/3/5-subtype-selective analogues.Correlating the biological results and NMR studies led to the identification of the side chains of DPhe2,DTrp8, and Lys9 as the necessary components of the sst2 pharmacophore. This is the first study to show thatthe aromatic ring at position 7 (Phe7) is not critical for sst2 binding and that it plays an important role in sst3and sst5 binding. This pharmacophore is, therefore, different from that proposed by others for sst2/3/5 analogues.