Synthesis and investigations of double-pharmacophore ligands for treatment of chronic and neuropathic pain

Ruben Vardanyan; Gokhale Vijay; Gary S. Nichol; Lu Liu; Isuru Kumarasinghe; Peg Davis; Todd Vanderah; Frank Porreca; Josephine Lai; Victor J. Hruby

doi:10.1016/j.bmc.2009.05.065

Synthesis and investigations of double-pharmacophore ligands for treatment of chronic and neuropathic pain

Ruben Vardanyan^*, Gokhale Vijay, Gary S. Nichol, Lu Liu, Isuru Kumarasinghe, Peg Davis, Todd Vanderah, Frank Porreca, Josephine Lai, Victor J. Hruby

^*Corresponding author for this work

School of Chemistry

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

Abstract

Acids 9a-f as possible bivalent ligands designed as a structural combination of opioid μ-agonist (Fentanyl) and NSAID (Indomethacin) activities and produced compounds which were tested as analgesics. The obtained series of compounds exhibits low affinity and activity both at opioid receptors and as cyclooxygenase (COX) inhibitors. One explanation of the weak opioid activity could be stereochemical peculiarities of these bivalent compounds which differ significantly from the fentanyl skeleton. The absence of significant COX inhibitory properties could be explained by the required substitution of an acyl fragment in the indomethacin structure for 4-piperidyl.

Original language	English
Pages (from-to)	5044-5053
Number of pages	10
Journal	Bioorganic and Medicinal Chemistry
Volume	17
Issue number	14
DOIs	https://doi.org/10.1016/j.bmc.2009.05.065
Publication status	Published - 15 Jul 2009

Keywords / Materials (for Non-textual outputs)

Analgesics
Indole
NSAID
Opioids
Piperidine

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10.1016/j.bmc.2009.05.065

Cite this

@article{a596ccfd3e1946dfb2dd453e55cbfcc8,

title = "Synthesis and investigations of double-pharmacophore ligands for treatment of chronic and neuropathic pain",

abstract = "Acids 9a-f as possible bivalent ligands designed as a structural combination of opioid μ-agonist (Fentanyl) and NSAID (Indomethacin) activities and produced compounds which were tested as analgesics. The obtained series of compounds exhibits low affinity and activity both at opioid receptors and as cyclooxygenase (COX) inhibitors. One explanation of the weak opioid activity could be stereochemical peculiarities of these bivalent compounds which differ significantly from the fentanyl skeleton. The absence of significant COX inhibitory properties could be explained by the required substitution of an acyl fragment in the indomethacin structure for 4-piperidyl.",

keywords = "Analgesics, Indole, NSAID, Opioids, Piperidine",

author = "Ruben Vardanyan and Gokhale Vijay and Nichol, {Gary S.} and Lu Liu and Isuru Kumarasinghe and Peg Davis 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, DA06284 and DA 06789. The authors thank Ohannes Melemedjian, David Rankin, Nicole Schecter and Janice Oyarzo for technical assistance. ",

year = "2009",

month = jul,

day = "15",

doi = "10.1016/j.bmc.2009.05.065",

language = "English",

volume = "17",

pages = "5044--5053",

journal = "Bioorganic and Medicinal Chemistry",

issn = "0968-0896",

publisher = "Elsevier",

number = "14",

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TY - JOUR

T1 - Synthesis and investigations of double-pharmacophore ligands for treatment of chronic and neuropathic pain

AU - Vardanyan, Ruben

AU - Vijay, Gokhale

AU - Nichol, Gary S.

AU - Liu, Lu

AU - Kumarasinghe, Isuru

AU - Davis, Peg

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, DA06284 and DA 06789. The authors thank Ohannes Melemedjian, David Rankin, Nicole Schecter and Janice Oyarzo for technical assistance.

PY - 2009/7/15

Y1 - 2009/7/15

N2 - Acids 9a-f as possible bivalent ligands designed as a structural combination of opioid μ-agonist (Fentanyl) and NSAID (Indomethacin) activities and produced compounds which were tested as analgesics. The obtained series of compounds exhibits low affinity and activity both at opioid receptors and as cyclooxygenase (COX) inhibitors. One explanation of the weak opioid activity could be stereochemical peculiarities of these bivalent compounds which differ significantly from the fentanyl skeleton. The absence of significant COX inhibitory properties could be explained by the required substitution of an acyl fragment in the indomethacin structure for 4-piperidyl.

AB - Acids 9a-f as possible bivalent ligands designed as a structural combination of opioid μ-agonist (Fentanyl) and NSAID (Indomethacin) activities and produced compounds which were tested as analgesics. The obtained series of compounds exhibits low affinity and activity both at opioid receptors and as cyclooxygenase (COX) inhibitors. One explanation of the weak opioid activity could be stereochemical peculiarities of these bivalent compounds which differ significantly from the fentanyl skeleton. The absence of significant COX inhibitory properties could be explained by the required substitution of an acyl fragment in the indomethacin structure for 4-piperidyl.

KW - Analgesics

KW - Indole

KW - NSAID

KW - Opioids

KW - Piperidine

U2 - 10.1016/j.bmc.2009.05.065

DO - 10.1016/j.bmc.2009.05.065

M3 - Article

C2 - 19540763

AN - SCOPUS:67650091754

SN - 0968-0896

VL - 17

SP - 5044

EP - 5053

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

IS - 14

ER -

Synthesis and investigations of double-pharmacophore ligands for treatment of chronic and neuropathic pain

Abstract

Keywords / Materials (for Non-textual outputs)

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