Novel sst2-selective somatostatin agonists.: Three-dimensional consensus structure by NMR

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/Phe(2)-c[Cys(3)-Xxx(7)-DTrp(8)-Lys(9)-Thr(10)-Cys(14)]-Thr-NH2 (the numbering refers to the position in native SRIF), with Xxx(7) being Ala/Aph, exhibit potent and highly selective binding to human SRIF type 2 (sst(2)) receptors. The backbone of these sst(2)-selective analogues have the usual type-II', beta-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 DPhe(2), DTrp(8), and Lys(9) as the necessary components of the sst(2) pharmacophore. This is the first study to show that the aromatic ring at position 7 (Phe(7)) is not critical for sst(2) binding and that it plays an important role in sst(3) and sst(5) binding. This pharmacophore is, therefore, different from that proposed by others for sst(2/3/5) analogues.