Discovery of diphenyl amine based sodium channel blockers, effective against hNav1.2

Debjani P. Hudgens; Catherine Taylor; Timothy W. Batts; Manoj K. Patel; Milton L. Brown

doi:10.1016/j.bmc.2006.09.010

Discovery of diphenyl amine based sodium channel blockers, effective against hNa_v1.2

Debjani P. Hudgens, Catherine Taylor, Timothy W. Batts, Manoj K. Patel, Milton L. Brown

Earl E. Bakken Medical Device Center

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

16 Scopus citations

Abstract

The development of new therapies for chronic pain is an area of unmet medical need. Central to pathways of chronic pain is the upregulation of voltage-gated sodium channels. The use of tricyclic antidepressants, which also have sodium channel activity, in chronic pain therapy prompted us to develop novel compounds from this scaffold. Herein, we show that the tricyclic moiety is not needed for effective inhibition of the [³H]-BTX binding site and sodium currents of hNa_v1.2. Our lead compound 6, containing a diphenyl amine motif, demonstrated a 53% inhibitory block of Na_v1.2 currents at 10 μM, which is greater than 50% increase in current block in comparison to the amitriptyline standard. Altogether our study establishes that the tricyclic motif is unnecessary for hNa_v1.2 activity and modification of the amine portion is detrimental to sodium channel block.

Original language	English (US)
Pages (from-to)	8366-8378
Number of pages	13
Journal	Bioorganic and Medicinal Chemistry
Volume	14
Issue number	24
DOIs	https://doi.org/10.1016/j.bmc.2006.09.010
State	Published - Dec 15 2006

Bibliographical note

Funding Information:
We thank NovaScreen, Inc. for technical support on the [ 3 H]-BTX studies, as well as Dr. H.A. Hartmann for the kind gift of HEK 293 cells stably expressing hNa v 1.2. We would also like to thank the National Institutes of Health for financial support through NIH Grant 1RO1CA105435-01 and the Georgetown Drug Discovery Program.

Keywords

Amitriptyline
Diphenyl amine
Neuropathic pain
Sodium channel blockers

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abstract = "The development of new therapies for chronic pain is an area of unmet medical need. Central to pathways of chronic pain is the upregulation of voltage-gated sodium channels. The use of tricyclic antidepressants, which also have sodium channel activity, in chronic pain therapy prompted us to develop novel compounds from this scaffold. Herein, we show that the tricyclic moiety is not needed for effective inhibition of the [3H]-BTX binding site and sodium currents of hNav1.2. Our lead compound 6, containing a diphenyl amine motif, demonstrated a 53% inhibitory block of Nav1.2 currents at 10 μM, which is greater than 50% increase in current block in comparison to the amitriptyline standard. Altogether our study establishes that the tricyclic motif is unnecessary for hNav1.2 activity and modification of the amine portion is detrimental to sodium channel block.",

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