Synthesis of bicyclic dipeptide mimetics for the cholecystokinin and opioid receptors

John M. Ndungu; Xuyuan Gu; Dustin E. Gross; James P. Cain; Michael D. Carducci; Victor J. Hruby

doi:10.1016/j.tetlet.2004.03.146

Synthesis of bicyclic dipeptide mimetics for the cholecystokinin and opioid receptors

John M. Ndungu, Xuyuan Gu, Dustin E. Gross, James P. Cain, Michael D. Carducci, Victor J. Hruby

Research output: Contribution to journal › Article › peer-review

12 Scopus citations

Abstract

The cholecystokinin C-terminal octapeptide analogue H-Asp-Tyr-D-Phe-Gly- Trp-(N-Me)-Nle-Asp-Phe-NH₂ (SNF 9007) is a potent and selective ligand for both the CCK-B and δ-opioid receptors. To constrain the peptide into the biologically active conformation(s), bicyclic dipeptide mimetics for Nle-Gly and homoPhe-Gly were designed and synthesized from β-substituted aspartic acids. Alkylation of L-aspartic acid using lithium bis(trimethylsilyl) amide (LHMDS) in the presence of hexamethylphosphoramide (HMPA) gave β-substituted aspartic acids, with the major product being the (2S,3R) isomer. Additional isomers of Nle-Gly bicyclic dipeptide mimetic were obtained via the Kazmaier-Claisen rearrangement reaction. The stereochemistries of the bicyclic dipeptide mimetics were assigned by X-ray and NMR.

Original language	English (US)
Pages (from-to)	4139-4142
Number of pages	4
Journal	Tetrahedron Letters
Volume	45
Issue number	21
DOIs	https://doi.org/10.1016/j.tetlet.2004.03.146
State	Published - May 17 2004
Externally published	Yes

Keywords

Bicyclic dipeptide
Cholecystokinin
Constrained peptides
Kazmaier-Claisen rearrangement
β-Substituted aspartic acid

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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10.1016/j.tetlet.2004.03.146

Cite this

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title = "Synthesis of bicyclic dipeptide mimetics for the cholecystokinin and opioid receptors",

abstract = "The cholecystokinin C-terminal octapeptide analogue H-Asp-Tyr-D-Phe-Gly- Trp-(N-Me)-Nle-Asp-Phe-NH2 (SNF 9007) is a potent and selective ligand for both the CCK-B and δ-opioid receptors. To constrain the peptide into the biologically active conformation(s), bicyclic dipeptide mimetics for Nle-Gly and homoPhe-Gly were designed and synthesized from β-substituted aspartic acids. Alkylation of L-aspartic acid using lithium bis(trimethylsilyl) amide (LHMDS) in the presence of hexamethylphosphoramide (HMPA) gave β-substituted aspartic acids, with the major product being the (2S,3R) isomer. Additional isomers of Nle-Gly bicyclic dipeptide mimetic were obtained via the Kazmaier-Claisen rearrangement reaction. The stereochemistries of the bicyclic dipeptide mimetics were assigned by X-ray and NMR.",

keywords = "Bicyclic dipeptide, Cholecystokinin, Constrained peptides, Kazmaier-Claisen rearrangement, β-Substituted aspartic acid",

author = "Ndungu, {John M.} and Xuyuan Gu and Gross, {Dustin E.} and Cain, {James P.} and Carducci, {Michael D.} and Hruby, {Victor J.}",

note = "Funding Information: This work was supported by US Public Health Service (DA 12394 and 13449). The NMR spectra were acquired using a DRX 500 MHz spectrometer, which was obtained by a grant from the NSF(9729350). The views expressed in this article are those of the authors and are not necessarily those of USPHS.",

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language = "English (US)",

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T1 - Synthesis of bicyclic dipeptide mimetics for the cholecystokinin and opioid receptors

AU - Ndungu, John M.

AU - Gu, Xuyuan

AU - Gross, Dustin E.

AU - Cain, James P.

AU - Carducci, Michael D.

AU - Hruby, Victor J.

N1 - Funding Information: This work was supported by US Public Health Service (DA 12394 and 13449). The NMR spectra were acquired using a DRX 500 MHz spectrometer, which was obtained by a grant from the NSF(9729350). The views expressed in this article are those of the authors and are not necessarily those of USPHS.

PY - 2004/5/17

Y1 - 2004/5/17

N2 - The cholecystokinin C-terminal octapeptide analogue H-Asp-Tyr-D-Phe-Gly- Trp-(N-Me)-Nle-Asp-Phe-NH2 (SNF 9007) is a potent and selective ligand for both the CCK-B and δ-opioid receptors. To constrain the peptide into the biologically active conformation(s), bicyclic dipeptide mimetics for Nle-Gly and homoPhe-Gly were designed and synthesized from β-substituted aspartic acids. Alkylation of L-aspartic acid using lithium bis(trimethylsilyl) amide (LHMDS) in the presence of hexamethylphosphoramide (HMPA) gave β-substituted aspartic acids, with the major product being the (2S,3R) isomer. Additional isomers of Nle-Gly bicyclic dipeptide mimetic were obtained via the Kazmaier-Claisen rearrangement reaction. The stereochemistries of the bicyclic dipeptide mimetics were assigned by X-ray and NMR.

AB - The cholecystokinin C-terminal octapeptide analogue H-Asp-Tyr-D-Phe-Gly- Trp-(N-Me)-Nle-Asp-Phe-NH2 (SNF 9007) is a potent and selective ligand for both the CCK-B and δ-opioid receptors. To constrain the peptide into the biologically active conformation(s), bicyclic dipeptide mimetics for Nle-Gly and homoPhe-Gly were designed and synthesized from β-substituted aspartic acids. Alkylation of L-aspartic acid using lithium bis(trimethylsilyl) amide (LHMDS) in the presence of hexamethylphosphoramide (HMPA) gave β-substituted aspartic acids, with the major product being the (2S,3R) isomer. Additional isomers of Nle-Gly bicyclic dipeptide mimetic were obtained via the Kazmaier-Claisen rearrangement reaction. The stereochemistries of the bicyclic dipeptide mimetics were assigned by X-ray and NMR.

KW - Bicyclic dipeptide

KW - Cholecystokinin

KW - Constrained peptides

KW - Kazmaier-Claisen rearrangement

KW - β-Substituted aspartic acid

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Synthesis of bicyclic dipeptide mimetics for the cholecystokinin and opioid receptors

Abstract

Keywords

ASJC Scopus subject areas

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CCDC 245052: Experimental Crystal Structure Determination

CCDC 245053: Experimental Crystal Structure Determination

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Synthesis of bicyclic dipeptide mimetics for the cholecystokinin and opioid receptors

Abstract

Keywords

ASJC Scopus subject areas

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CCDC 245052: Experimental Crystal Structure Determination

CCDC 245053: Experimental Crystal Structure Determination

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