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

Grace, Christy Rani R; Erchegyi, Judit; Koerber, Steven C; Reubi, Jean Claude; Rivier, Jean; Riek, Roland (2006). Novel sst2-selective somatostatin agonists. Three-dimensional consensus structure by NMR. Journal of medicinal chemistry, 49(15), pp. 4487-96. Easton, Pa.: American Chemical Society 10.1021/jm060363v

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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' beta-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 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 sst2/3/5 analogues.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Service Sector > Institute of Pathology
UniBE Contributor:	Reubi-Kattenbusch, Jean-Claude
Subjects:	500 Science > 570 Life sciences; biology 600 Technology > 610 Medicine & health
ISSN:	0022-2623
ISBN:	16854054
Publisher:	American Chemical Society
Language:	English
Submitter:	Factscience Import
Date Deposited:	04 Oct 2013 14:48
Last Modified:	05 Dec 2022 14:15
Publisher DOI:	10.1021/jm060363v
PubMed ID:	16854054
Web of Science ID:	000239141500007
URI:	https://boris.unibe.ch/id/eprint/20296 (FactScience: 3552)