Ring size in octreotide amide modulates differently agonist versus antagonist binding affinity and selectivity

Grace, Christy Rani R; Erchegyi, Judit; Samant, Manoj; Cescato, Renzo; Piccand, Veronique; Riek, Roland; Reubi, Jean Claude; Rivier, Jean E (2008). Ring size in octreotide amide modulates differently agonist versus antagonist binding affinity and selectivity. Journal of medicinal chemistry, 51(9), pp. 2676-81. Easton, Pa.: American Chemical Society 10.1021/jm701445q

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H-DPhe (2)-c[Cys (3)-Phe (7)-DTrp (8)-Lys (9)-Thr (10)-Cys (14)]-Thr (15)-NH2 (1) (a somatostatin agonist, SRIF numbering) and H-Cpa (2)-c[DCys (3)-Tyr (7)-DTrp (8)-Lys (9)-Thr (10)-Cys (14)]-Nal (15)-NH2 (4) (a somatostatin antagonist) are based on the structure of octreotide that binds to three somatostatin receptor subtypes (sst 2/3/5) with significant binding affinity. Analogues of 1 and 4 were synthesized with norcysteine (Ncy), homocysteine (Hcy), or D-homocysteine (DHcy) at positions 3 and/or 14. Introducing Ncy at positions 3 and 14 constrained the backbone flexibility, resulting in loss of binding affinity at all sst s. The introduction of Hcy at positions 3 and 14 improved selectivity for sst 2 as a result of significant loss of binding affinity at the other sst s. Substitution by DHcy at position 3 in the antagonist scaffold (5), on the other hand, resulted in a significant loss of binding affinity at sst 2 and sst 3 as compared to the different affinities of the parent compound (4). The 3D NMR structures of the analogues in dimethylsulfoxide are consistent with the observed binding affinities.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology
04 Faculty of Medicine > Service Sector > Institute of Pathology > Tumour Pathology

UniBE Contributor:

Cescato, Renzo; Piccand, Véronique and Reubi, Jean-Claude

ISSN:

0022-2623

ISBN:

18410083

Publisher:

American Chemical Society

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 15:02

Last Modified:

04 May 2014 23:19

Publisher DOI:

10.1021/jm701445q

PubMed ID:

18410083

Web of Science ID:

000255500000013

URI:

https://boris.unibe.ch/id/eprint/27065 (FactScience: 101627)

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