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.
Bibliographical noteFunding 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.
Copyright 2008 Elsevier B.V., All rights reserved.
- Diphenyl amine
- Neuropathic pain
- Sodium channel blockers