Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 14, Issue 24, Pages 8366-8378Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2006.09.010
Keywords
diphenyl amine; neuropathic pain; sodium channel blockers; amitriptyline
Funding
- NCI NIH HHS [R01 CA105435, R01 CA105435-05, R01 CA105435-06, 1R01CA105435-01] Funding Source: Medline
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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 [H-3]-BTX binding site and sodium currents of hNa(v)1.2. Our lead compound 6, containing a diphenyl amine motif, demonstrated a 53% inhibitory block of Na(v)1.2 currents at 10 mu M, 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(v)1.2 activity and modification of the amine portion is detrimental to sodium channel block. (c) 2006 Elsevier Ltd. All rights reserved.
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