The biological activity and metabolic stability of peptidic bifunctional compounds that are opioid receptor agonists and neurokinin-1 receptor antagonists with a cystine moiety

Takashi Yamamoto; Padma Nair; Shou wu Ma; Peg Davis; Henry I. Yamamura; Todd W. Vanderah; Frank Porreca; Josephine Lai; Victor J. Hruby

doi:10.1016/j.bmc.2009.08.035

The biological activity and metabolic stability of peptidic bifunctional compounds that are opioid receptor agonists and neurokinin-1 receptor antagonists with a cystine moiety

Takashi Yamamoto
, Padma Nair
, Shou wu Ma
, Peg Davis
, Henry I. Yamamura
, Todd W. Vanderah
, Frank Porreca
, Josephine Lai
, Victor J. Hruby

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

30 Scopus citations

Abstract

In order to improve metabolic stability, a ring structure with a cystine moiety was introduced into TY027 (Tyr-d-Ala-Gly-Phe-Met-Pro-Leu-Trp-NH-[3′,5′-(CF₃)₂Bzl]), which is a lead compound of our developing bifunctional peptide possessing opioid agonist and NK1 antagonist activities. TY038 (Tyr-cyclo[d-Cys-Gly-Phe-Met-Pro-d-Cys]-Trp-NH-[3′,5′-(CF₃)₂Bzl]) was found as a highly selective δ opioid agonist over μ receptor in conventional tissue-based assays, together with an effective NK1 antagonist activity and good metabolic stability with more than 24 h half life in rat plasma.

Original language	English (US)
Pages (from-to)	7337-7343
Number of pages	7
Journal	Bioorganic and Medicinal Chemistry
Volume	17
Issue number	20
DOIs	https://doi.org/10.1016/j.bmc.2009.08.035
State	Published - Oct 15 2009

Keywords

Bifunctional compounds
Disulfide bond
Metabolic stability
Multivalent ligands
Neutokinin-1 antagonists
Opioid agonists

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmc.2009.08.035

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Yamamoto, T., Nair, P., Ma, S. W., Davis, P., Yamamura, H. I., Vanderah, T. W., Porreca, F., Lai, J., & Hruby, V. J. (2009). The biological activity and metabolic stability of peptidic bifunctional compounds that are opioid receptor agonists and neurokinin-1 receptor antagonists with a cystine moiety. Bioorganic and Medicinal Chemistry, 17(20), 7337-7343. https://doi.org/10.1016/j.bmc.2009.08.035

The biological activity and metabolic stability of peptidic bifunctional compounds that are opioid receptor agonists and neurokinin-1 receptor antagonists with a cystine moiety. / Yamamoto, Takashi; Nair, Padma; Ma, Shou wu et al.
In: Bioorganic and Medicinal Chemistry, Vol. 17, No. 20, 15.10.2009, p. 7337-7343.

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

Yamamoto, T, Nair, P, Ma, SW, Davis, P, Yamamura, HI, Vanderah, TW , Porreca, F, Lai, J & Hruby, VJ 2009, 'The biological activity and metabolic stability of peptidic bifunctional compounds that are opioid receptor agonists and neurokinin-1 receptor antagonists with a cystine moiety', Bioorganic and Medicinal Chemistry, vol. 17, no. 20, pp. 7337-7343. https://doi.org/10.1016/j.bmc.2009.08.035

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title = "The biological activity and metabolic stability of peptidic bifunctional compounds that are opioid receptor agonists and neurokinin-1 receptor antagonists with a cystine moiety",

abstract = "In order to improve metabolic stability, a ring structure with a cystine moiety was introduced into TY027 (Tyr-d-Ala-Gly-Phe-Met-Pro-Leu-Trp-NH-[3′,5′-(CF3)2Bzl]), which is a lead compound of our developing bifunctional peptide possessing opioid agonist and NK1 antagonist activities. TY038 (Tyr-cyclo[d-Cys-Gly-Phe-Met-Pro-d-Cys]-Trp-NH-[3′,5′-(CF3)2Bzl]) was found as a highly selective δ opioid agonist over μ receptor in conventional tissue-based assays, together with an effective NK1 antagonist activity and good metabolic stability with more than 24 h half life in rat plasma.",

keywords = "Bifunctional compounds, Disulfide bond, Metabolic stability, Multivalent ligands, Neutokinin-1 antagonists, Opioid agonists",

author = "Takashi Yamamoto and Padma Nair and Ma, \{Shou wu\} and Peg Davis and Yamamura, \{Henry I.\} and Vanderah, \{Todd W.\} and Frank Porreca and Josephine Lai and Hruby, \{Victor J.\}",

note = "Funding Information: The work was supported by grants from the USDHS , National Institute on Drug Abuse , DA-13449 and DA-06284 . We thank Ms. Magdalena Kaczmarska for culturing cells, and the University of Arizona Mass Spectrometry Facility for the mass spectra measurements. We express appreciation to Ms. Margie Colie and Ms. Brigid Blazek for assistance with the manuscript. ",

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AU - Yamamura, Henry I.

AU - Vanderah, Todd W.

AU - Porreca, Frank

AU - Lai, Josephine

AU - Hruby, Victor J.

N1 - Funding Information: The work was supported by grants from the USDHS , National Institute on Drug Abuse , DA-13449 and DA-06284 . We thank Ms. Magdalena Kaczmarska for culturing cells, and the University of Arizona Mass Spectrometry Facility for the mass spectra measurements. We express appreciation to Ms. Margie Colie and Ms. Brigid Blazek for assistance with the manuscript.

PY - 2009/10/15

Y1 - 2009/10/15

N2 - In order to improve metabolic stability, a ring structure with a cystine moiety was introduced into TY027 (Tyr-d-Ala-Gly-Phe-Met-Pro-Leu-Trp-NH-[3′,5′-(CF3)2Bzl]), which is a lead compound of our developing bifunctional peptide possessing opioid agonist and NK1 antagonist activities. TY038 (Tyr-cyclo[d-Cys-Gly-Phe-Met-Pro-d-Cys]-Trp-NH-[3′,5′-(CF3)2Bzl]) was found as a highly selective δ opioid agonist over μ receptor in conventional tissue-based assays, together with an effective NK1 antagonist activity and good metabolic stability with more than 24 h half life in rat plasma.

AB - In order to improve metabolic stability, a ring structure with a cystine moiety was introduced into TY027 (Tyr-d-Ala-Gly-Phe-Met-Pro-Leu-Trp-NH-[3′,5′-(CF3)2Bzl]), which is a lead compound of our developing bifunctional peptide possessing opioid agonist and NK1 antagonist activities. TY038 (Tyr-cyclo[d-Cys-Gly-Phe-Met-Pro-d-Cys]-Trp-NH-[3′,5′-(CF3)2Bzl]) was found as a highly selective δ opioid agonist over μ receptor in conventional tissue-based assays, together with an effective NK1 antagonist activity and good metabolic stability with more than 24 h half life in rat plasma.

KW - Bifunctional compounds

KW - Disulfide bond

KW - Metabolic stability

KW - Multivalent ligands

KW - Neutokinin-1 antagonists

KW - Opioid agonists

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The biological activity and metabolic stability of peptidic bifunctional compounds that are opioid receptor agonists and neurokinin-1 receptor antagonists with a cystine moiety

Abstract

Keywords

ASJC Scopus subject areas

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