Synthesis and biological evaluation of new opioid agonist and neurokinin-1 antagonist bivalent ligands

Ruben Vardanyan; Vlad K. Kumirov; Gary S. Nichol; Peg Davis; Erika Liktor-Busa; David Rankin; Eva Varga; Todd Vanderah; Frank Porreca; Josephine Lai; Victor J. Hruby

doi:10.1016/j.bmc.2011.08.027

Synthesis and biological evaluation of new opioid agonist and neurokinin-1 antagonist bivalent ligands

Ruben Vardanyan, Vlad K. Kumirov, Gary S. Nichol, Peg Davis, Erika Liktor-Busa, David Rankin, Eva Varga, Todd Vanderah, Frank Porreca, Josephine Lai, Victor J. Hruby

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

22 Scopus citations

Abstract

Newly designed bivalent ligands - opioid agonist/NK1-antagonists have been synthesized. The synthesis of new starting materials - carboxy-derivatives of Fentanyl (1a-1c) was developed. These products have been transformed to 'isoimidium perchlorates' (2a-c). The new isoimidium perchlorates have been successfully implemented in nucleophilic addition reactions, with l-tryptophan 3,5-bis(trifluoromethyl)benzyl ester to give the target compounds - amides (3a-c). Perchlorates (2a-c) successfully undergo reactions with other nucleophiles such as alcohols, amines or hydrazines. The obtained compound 3b exhibited μ-opioid agonist activity and NK1-antagonist activity and may serve as a useful lead compound for the further design of a new series of opioid agonist/NK1-antagonist compounds.

Original language	English (US)
Pages (from-to)	6135-6142
Number of pages	8
Journal	Bioorganic and Medicinal Chemistry
Volume	19
Issue number	20
DOIs	https://doi.org/10.1016/j.bmc.2011.08.027
State	Published - Oct 15 2011

Keywords

Analgesic
Bivalent ligands
Fentanyl
NK1 antagonist
μ-Opioids

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.2011.08.027

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title = "Synthesis and biological evaluation of new opioid agonist and neurokinin-1 antagonist bivalent ligands",

abstract = "Newly designed bivalent ligands - opioid agonist/NK1-antagonists have been synthesized. The synthesis of new starting materials - carboxy-derivatives of Fentanyl (1a-1c) was developed. These products have been transformed to 'isoimidium perchlorates' (2a-c). The new isoimidium perchlorates have been successfully implemented in nucleophilic addition reactions, with l-tryptophan 3,5-bis(trifluoromethyl)benzyl ester to give the target compounds - amides (3a-c). Perchlorates (2a-c) successfully undergo reactions with other nucleophiles such as alcohols, amines or hydrazines. The obtained compound 3b exhibited μ-opioid agonist activity and NK1-antagonist activity and may serve as a useful lead compound for the further design of a new series of opioid agonist/NK1-antagonist compounds.",

keywords = "Analgesic, Bivalent ligands, Fentanyl, NK1 antagonist, μ-Opioids",

author = "Ruben Vardanyan and Kumirov, {Vlad K.} and Nichol, {Gary S.} and Peg Davis and Erika Liktor-Busa and David Rankin and Eva Varga and Todd Vanderah and Frank Porreca and Josephine Lai and Hruby, {Victor J.}",

note = "Funding Information: This work was supported from the U.S. Public National Institute of Health DA 13449, DA 06284 and DA 06789. ",

year = "2011",

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doi = "10.1016/j.bmc.2011.08.027",

language = "English (US)",

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AU - Vardanyan, Ruben

AU - Kumirov, Vlad K.

AU - Nichol, Gary S.

AU - Davis, Peg

AU - Liktor-Busa, Erika

AU - Rankin, David

AU - Varga, Eva

AU - Vanderah, Todd

AU - Porreca, Frank

AU - Lai, Josephine

AU - Hruby, Victor J.

N1 - Funding Information: This work was supported from the U.S. Public National Institute of Health DA 13449, DA 06284 and DA 06789.

PY - 2011/10/15

Y1 - 2011/10/15

N2 - Newly designed bivalent ligands - opioid agonist/NK1-antagonists have been synthesized. The synthesis of new starting materials - carboxy-derivatives of Fentanyl (1a-1c) was developed. These products have been transformed to 'isoimidium perchlorates' (2a-c). The new isoimidium perchlorates have been successfully implemented in nucleophilic addition reactions, with l-tryptophan 3,5-bis(trifluoromethyl)benzyl ester to give the target compounds - amides (3a-c). Perchlorates (2a-c) successfully undergo reactions with other nucleophiles such as alcohols, amines or hydrazines. The obtained compound 3b exhibited μ-opioid agonist activity and NK1-antagonist activity and may serve as a useful lead compound for the further design of a new series of opioid agonist/NK1-antagonist compounds.

AB - Newly designed bivalent ligands - opioid agonist/NK1-antagonists have been synthesized. The synthesis of new starting materials - carboxy-derivatives of Fentanyl (1a-1c) was developed. These products have been transformed to 'isoimidium perchlorates' (2a-c). The new isoimidium perchlorates have been successfully implemented in nucleophilic addition reactions, with l-tryptophan 3,5-bis(trifluoromethyl)benzyl ester to give the target compounds - amides (3a-c). Perchlorates (2a-c) successfully undergo reactions with other nucleophiles such as alcohols, amines or hydrazines. The obtained compound 3b exhibited μ-opioid agonist activity and NK1-antagonist activity and may serve as a useful lead compound for the further design of a new series of opioid agonist/NK1-antagonist compounds.

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KW - NK1 antagonist

KW - μ-Opioids

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Synthesis and biological evaluation of new opioid agonist and neurokinin-1 antagonist bivalent ligands

Abstract

Keywords

ASJC Scopus subject areas

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