N-imidazolebenzyl-histidine substitution in somatostatin and in its octapeptide analogue modulates receptor selectivity and function

Erchegyi, Judit; Cescato, Renzo; Waser, Beatrice; Rivier, Jean E; Reubi, Jean Claude (2011). N-imidazolebenzyl-histidine substitution in somatostatin and in its octapeptide analogue modulates receptor selectivity and function. Journal of medicinal chemistry, 54(17), pp. 5981-7. Easton, Pa.: American Chemical Society 10.1021/jm200307v

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Despite 3 decades of focused chemical, biological, structural, and clinical developments, unusual properties of somatostatin (SRIF, 1) analogues are still being uncovered. Here we report the unexpected functional properties of 1 and the octapeptide cyclo(3-14)H-Cys-Phe-Phe-Trp(8)-Lys-Thr-Phe-Cys-OH (somatostatin numbering; OLT-8, 9) substituted by imBzl-l- or -d-His at position 8. These analogues were tested for their binding affinity to the five human somatostatin receptors (sst(1-5)), as well as for their functional properties (or functionalities) in an sst(3) internalization assay and in an sst(3) luciferase reporter gene assay. While substitution of Trp(8) in somatostatin by imBzl-l- or -d-His(8) results in sst(3) selectivity, substitution of Trp(8) in the octapeptide 9 by imBzl-l- or -d-His(8) results in loss of binding affinity for sst(1,2,4,5) and a radical functional switch from agonist to antagonist.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology

UniBE Contributor:

Cescato, Renzo; Waser, Beatrice and Reubi, Jean-Claude

ISSN:

0022-2623

Publisher:

American Chemical Society

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:18

Last Modified:

06 Dec 2013 13:26

Publisher DOI:

10.1021/jm200307v

PubMed ID:

21806016

Web of Science ID:

000294385700002

URI:

https://boris.unibe.ch/id/eprint/5553 (FactScience: 210307)

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