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Synthesis of potent cyclic hexapeptide NK-1 antagonists. Use of a minilibrary in transforming a peptidal somatostatin receptor ligand into an NK-1 receptor ligand via a polyvalent peptidomimetic.

Abstract：

:The endogenous peptides somatostatin (SRIF) and substance P comprise very different structures. Although both bind G-protein-coupled receptors, the SRIF receptors (SSTR 1-5) recognize SRIF and related peptides which retain its beta-turn such as the potent cyclic hexapeptide SRIF agonist L-363,301 (6a), but not substance P. Conversely the NK-1 receptor binds substance P but not the above ligands. In contrast, the beta-D-glucosides 1 and 2, designed to mimic the beta-turn of 6a, bind both receptors. This observation led us to attempt the conversion of 6a into the first potent, selective cyclic hexapeptide ligand for the NK-1 receptor. To this end, we combined design with a minilibrary approach. The goal was accomplished with surprising ease, leading to the NK-1 receptor antagonist 9 (IC50 2.0 +/- 0.4 nM). This demonstrates that peptidomimetics, incorporating in this case the promiscuous beta-D-glucose scaffold, can provide valuable clues about receptor similarities not revealed by their endogenous ligands. In addition, this work suggests that the use of libraries and rational design need not be mutually exclusive approaches to lead discovery.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Hirschmann R,Yao W,Cascieri MA,Strader CD,Maechler L,Cichy-Knight MA,Hynes J Jr,van Rijn RD,Sprengeler PA,Smith AB 3rd

doi

10.1021/jm960281e

subject

Has Abstract

pub_date

1996-06-21 00:00:00

pages

2441-8

issue

13

eissn

0022-2623

issn

1520-4804

pii

jm960281e

journal_volume

39

pub_type

杂志文章

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