First-in-class, dual-action, 3,5-disubstituted indole derivatives having human nitric oxide synthase (nNOS) and norepinephrine reuptake inhibitory (NERI) activity for the treatment of neuropathic pain

Gabriela Mladenova, Subhash C. Annedi, Jailall Ramnauth, Shawn P. Maddaford, Suman Rakhit, John S. Andrews, Dongqin Zhang, Frank Porreca

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

A family of different 3,5-disubstituted indole derivatives having 6-membered rings were designed, synthesized, and demonstrated inhibition of human nitric oxide synthase (NOS) with norepinephrine reuptake inhibitory activity (NERI). The structure-activity relationship (SAR) within the cyclohexane ring showed the cis-isomers to be more potent for neuronal NOS and selective over endothelial NOS compared to their trans-counterparts. Compounds, such as cis-(+)-37, exhibited dual nNOS and NET inhibition (IC 50 of 0.56 and 1.0 μM, respectively) and excellent selectivity (88-fold and 12-fold) over eNOS and iNOS, respectively. The lead compound (cis-(+)-37) showed lack of any direct vasoconstriction or inhibition of ACh-mediated vasorelaxation in isolated human coronary arteries. Additionally, cis-(+)-37 was effective at reversing both allodynia and thermal hyperalgesia in a standard Chung (spinal nerve ligation) rat neuropathic pain model. Overall, the data suggest that cis-(+)-37 is a promising dual action development candidate having therapeutic potential for the treatment of neuropathic pain.

Original languageEnglish (US)
Pages (from-to)3488-3501
Number of pages14
JournalJournal of Medicinal Chemistry
Volume55
Issue number7
DOIs
StatePublished - Apr 12 2012

Fingerprint

Hyperalgesia
Neuralgia
Nitric Oxide Synthase
Norepinephrine
Spinal Nerves
Nitric Oxide Synthase Type I
Nitric Oxide Synthase Type III
Structure-Activity Relationship
Vasoconstriction
Vasodilation
Ligation
Coronary Vessels
Therapeutics
indole
Cyclohexane
Lead

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

First-in-class, dual-action, 3,5-disubstituted indole derivatives having human nitric oxide synthase (nNOS) and norepinephrine reuptake inhibitory (NERI) activity for the treatment of neuropathic pain. / Mladenova, Gabriela; Annedi, Subhash C.; Ramnauth, Jailall; Maddaford, Shawn P.; Rakhit, Suman; Andrews, John S.; Zhang, Dongqin; Porreca, Frank.

In: Journal of Medicinal Chemistry, Vol. 55, No. 7, 12.04.2012, p. 3488-3501.

Research output: Contribution to journalArticle

Mladenova, Gabriela ; Annedi, Subhash C. ; Ramnauth, Jailall ; Maddaford, Shawn P. ; Rakhit, Suman ; Andrews, John S. ; Zhang, Dongqin ; Porreca, Frank. / First-in-class, dual-action, 3,5-disubstituted indole derivatives having human nitric oxide synthase (nNOS) and norepinephrine reuptake inhibitory (NERI) activity for the treatment of neuropathic pain. In: Journal of Medicinal Chemistry. 2012 ; Vol. 55, No. 7. pp. 3488-3501.
@article{07c5dda48f7c4ca2a1730a38e678272b,
title = "First-in-class, dual-action, 3,5-disubstituted indole derivatives having human nitric oxide synthase (nNOS) and norepinephrine reuptake inhibitory (NERI) activity for the treatment of neuropathic pain",
abstract = "A family of different 3,5-disubstituted indole derivatives having 6-membered rings were designed, synthesized, and demonstrated inhibition of human nitric oxide synthase (NOS) with norepinephrine reuptake inhibitory activity (NERI). The structure-activity relationship (SAR) within the cyclohexane ring showed the cis-isomers to be more potent for neuronal NOS and selective over endothelial NOS compared to their trans-counterparts. Compounds, such as cis-(+)-37, exhibited dual nNOS and NET inhibition (IC 50 of 0.56 and 1.0 μM, respectively) and excellent selectivity (88-fold and 12-fold) over eNOS and iNOS, respectively. The lead compound (cis-(+)-37) showed lack of any direct vasoconstriction or inhibition of ACh-mediated vasorelaxation in isolated human coronary arteries. Additionally, cis-(+)-37 was effective at reversing both allodynia and thermal hyperalgesia in a standard Chung (spinal nerve ligation) rat neuropathic pain model. Overall, the data suggest that cis-(+)-37 is a promising dual action development candidate having therapeutic potential for the treatment of neuropathic pain.",
author = "Gabriela Mladenova and Annedi, {Subhash C.} and Jailall Ramnauth and Maddaford, {Shawn P.} and Suman Rakhit and Andrews, {John S.} and Dongqin Zhang and Frank Porreca",
year = "2012",
month = "4",
day = "12",
doi = "10.1021/jm300138g",
language = "English (US)",
volume = "55",
pages = "3488--3501",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "7",

}

TY - JOUR

T1 - First-in-class, dual-action, 3,5-disubstituted indole derivatives having human nitric oxide synthase (nNOS) and norepinephrine reuptake inhibitory (NERI) activity for the treatment of neuropathic pain

AU - Mladenova, Gabriela

AU - Annedi, Subhash C.

AU - Ramnauth, Jailall

AU - Maddaford, Shawn P.

AU - Rakhit, Suman

AU - Andrews, John S.

AU - Zhang, Dongqin

AU - Porreca, Frank

PY - 2012/4/12

Y1 - 2012/4/12

N2 - A family of different 3,5-disubstituted indole derivatives having 6-membered rings were designed, synthesized, and demonstrated inhibition of human nitric oxide synthase (NOS) with norepinephrine reuptake inhibitory activity (NERI). The structure-activity relationship (SAR) within the cyclohexane ring showed the cis-isomers to be more potent for neuronal NOS and selective over endothelial NOS compared to their trans-counterparts. Compounds, such as cis-(+)-37, exhibited dual nNOS and NET inhibition (IC 50 of 0.56 and 1.0 μM, respectively) and excellent selectivity (88-fold and 12-fold) over eNOS and iNOS, respectively. The lead compound (cis-(+)-37) showed lack of any direct vasoconstriction or inhibition of ACh-mediated vasorelaxation in isolated human coronary arteries. Additionally, cis-(+)-37 was effective at reversing both allodynia and thermal hyperalgesia in a standard Chung (spinal nerve ligation) rat neuropathic pain model. Overall, the data suggest that cis-(+)-37 is a promising dual action development candidate having therapeutic potential for the treatment of neuropathic pain.

AB - A family of different 3,5-disubstituted indole derivatives having 6-membered rings were designed, synthesized, and demonstrated inhibition of human nitric oxide synthase (NOS) with norepinephrine reuptake inhibitory activity (NERI). The structure-activity relationship (SAR) within the cyclohexane ring showed the cis-isomers to be more potent for neuronal NOS and selective over endothelial NOS compared to their trans-counterparts. Compounds, such as cis-(+)-37, exhibited dual nNOS and NET inhibition (IC 50 of 0.56 and 1.0 μM, respectively) and excellent selectivity (88-fold and 12-fold) over eNOS and iNOS, respectively. The lead compound (cis-(+)-37) showed lack of any direct vasoconstriction or inhibition of ACh-mediated vasorelaxation in isolated human coronary arteries. Additionally, cis-(+)-37 was effective at reversing both allodynia and thermal hyperalgesia in a standard Chung (spinal nerve ligation) rat neuropathic pain model. Overall, the data suggest that cis-(+)-37 is a promising dual action development candidate having therapeutic potential for the treatment of neuropathic pain.

UR - http://www.scopus.com/inward/record.url?scp=84859787097&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84859787097&partnerID=8YFLogxK

U2 - 10.1021/jm300138g

DO - 10.1021/jm300138g

M3 - Article

VL - 55

SP - 3488

EP - 3501

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 7

ER -