Novel sst2-Selective Somatostatin Agonists. Three-Dimensional Consensus Structure by NMR

Abstract

The 3D NMR structures of six octapeptide agonist analogues of somatostatin (SRIF) in the free form are described. 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 potent and highly selective binding to human SRIF type 2 (sst₂) receptors. The backbone of these sst₂-selective analogues have the usual type-II‘ β-turn reported in the literature for sst_2/3/5-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 that the aromatic ring at position 7 (Phe⁷) is not critical for sst₂ binding and that it plays an important role in sst₃ and sst₅ binding. This pharmacophore is, therefore, different from that proposed by others for sst_2/3/5 analogues.