Novel octreotide dicarba-analogues with high affinity and different selectivity for somatostatin receptors

Di Cianni, Alessandra; Carotenuto, Alfonso; Brancaccio, Diego; Novellino, Ettore; Reubi, Jean-Claude; Beetschen, Karin; Papini, Anna Maria; Ginanneschi, Mauro (2010). Novel octreotide dicarba-analogues with high affinity and different selectivity for somatostatin receptors. Journal of medicinal chemistry, 53(16), pp. 6188-97. Easton, Pa.: American Chemical Society 10.1021/jm1005868

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A limited set of novel octreotide dicarba-analogues with non-native aromatic side chains in positions 7 and/or 10 were synthesized. Their affinity toward the ssts1-5 was determined. Derivative 4 exhibited a pan-somatostatin activity, except sst4, and derivative 8 exhibited high affinity and selectivity toward sst5. Actually, compound 8 has similar sst5 affinity (IC50 4.9 nM) to SRIF-28 and octreotide. Structure-activity relationships suggest that the Z geometry of the double-bond bridge is that preferred by the receptors. The NMR study on the conformations of these compounds in SDS(-d25) micelles solution shows that all these analogues have the pharmacophore beta-turn spanning Xaa7-D-Trp8-Lys9-Yaa10 residues. Notably, the correlation between conformation families and affinity data strongly indicates that the sst5 selectivity is favored by a helical conformation involving the C-terminus triad, while a pan-SRIF mimic activity is based mainly on a conformational equilibrium between extended and folded conformational states.

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

Publisher:

American Chemical Society

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:09

Last Modified:

14 Oct 2019 17:00

Publisher DOI:

10.1021/jm1005868

PubMed ID:

20666484

Web of Science ID:

000280962700025

URI:

https://boris.unibe.ch/id/eprint/793 (FactScience: 200865)

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