Monosaccharide-based beta turn mimetics for the somatostatin and neurokinin-1 receptors.

Format:

Book

Thesis/Dissertation

Author/Creator:

McVaugh, Cheryl T.

Contributor:

Smith, Amos B., III, advisor.

Hirschmann, Ralph, advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Chemistry, Organic.

Biochemistry.

0487.

0490.

Penn dissertations--Chemistry.

Chemistry--Penn dissertations.

Local Subjects:

Penn dissertations--Chemistry.

Chemistry--Penn dissertations.

0487.

0490.

Physical Description:

349 pages

Contained In:

Dissertation Abstracts International 64-04B.

System Details:

Mode of access: World Wide Web.

text file

Summary:

This dissertation describes the design and synthesis of mono saccharide-based peptidomimetics for the somatostatin and neurokinin-1 receptors. The introductory chapter gives a brief overview of the use of carbohydrates as peptidomimetic scaffolds, with examples from the Hirschmann-Smith laboratories, as well as the laboratories of others.

In Chapter 1, the application of mono saccharide-based peptidomimetics at the human somatostatin subtype-4 (hSST4) receptor is discussed. Incorporation of heterocyclic substituents, such as pyridin-3-ylmethyl, pyrazin-2-ylmethyl and 2-fluoropyridin-3-ylmethyl (typified by (+)-1--2), at the C4 position of the glucose scaffold afforded an unexpected affinity enhancement. Evidence suggests that a hydrogen bond between the substituent and the hSST4 receptor is responsible for this affinity enhancement. Additionally, incorporation of an imidazole substituent at the C2 position afforded (-)-1--28, a 53 nM hSST4 ligand. Preparation of (-)-1--29 to explore this affinity-enhancement revealed that imidazole by itself is not enough to enhance affinity in this series, but the presence of pyridin-3-ylmethyl is required. This resulted is explained by conformational analysis wherein the exocyclic C-O bond is eclipsed.*

In Chapter 2, the affinity of (+)-0--1 for the neurokinin-1 receptor (hNK-1) is attempted to be explained through structural correlation with other classes of NK-1 receptor ligands. In Chapter 3 describes how optimization of the affinity of (+)-0--1 at the NK-1 receptor was accomplished by placing the side chains at different contiguous positions on the glucose scaffold; elucidation of the SAR of (-)-3--4 led to the discovery of 8 nM hNK-1 receptor ligand (-)-3--12. Finally, the radial symmetry inherent to the glucose scaffold is postulated to be a major contributing factor for the established usefulness of former in lead discovery.*

*Please refer to dissertation for diagrams.

Notes:

Thesis (Ph.D. in Chemistry) -- University of Pennsylvania, 2003.

Source: Dissertation Abstracts International, Volume: 64-04, Section: B, page: 1735.

Supervisors: Ralph Hirschmann; Amos B. Smith, III.

Local Notes:

School code: 0175.

ISBN:

9780496352043

Access Restriction:

Restricted for use by site license.