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Article

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

Christy Rani R. Grace,^† Judit Erchegyi,^‡ Steven C. Koerber,^‡ Jean Claude Reubi,^§ Jean Rivier,*^‡ and Roland Riek^†

Structural Biology Laboratory, The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, California 92037, and Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Berne, Berne, Switzerland

J. Med. Chem., 2006, 49 (15), pp 4487–4496

DOI: 10.1021/jm060363v

Publication Date (Web): July 1, 2006

†

Structural Biology Laboratory, The Salk Institute for Biological Studies.

‡

The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies.

University of Berne.

Corresponding author. Tel: (858) 453-4100. Fax: (858) 552-1546. E-mail: jrivier@salk.edu.

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.