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Design, Synthesis and Evaluation of Novel Isoform-Selective Sodium Channel Inhibi

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R43NS081887-01
Agency Tracking Number: R43NS081887
Amount: $236,235.00
Phase: Phase I
Program: SBIR
Solicitation Topic Code: NINDS
Solicitation Number: PA12-088
Timeline
Solicitation Year: 2013
Award Year: 2013
Award Start Date (Proposal Award Date): N/A
Award End Date (Contract End Date): N/A
Small Business Information
600 CASTLE HILL ROAD
REDWOOD CITY, CA 94061-1102
United States
DUNS: 962676495
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 JOHN MULCAHY
 (650) 368-6983
 JOHN.V.MULCAHY@GMAIL.COM
Business Contact
 GEORGE MILJANICH
Phone: (650) 368-6983
Email: GMILJANICH@COMCAST.NET
Research Institution
 Stub
Abstract

DESCRIPTION (provided by applicant): Side effects associated with opioid analgesics, such as nausea, drowsiness, respiratory depression, and potential for addiction, are motivating the design and development of new therapies for acute, subacute and chronic pain. Voltage-gated Na+ ion channels are integral membrane proteins responsible for the transmission of signals along electrically conducting cells. Ten mammalian genes have been sequenced, which encode ten distinct channel isoforms (NaV1.1-1.9 and NaX),each having unique gating properties, and cellular and tissue distribution patterns. Recent studies have correlated a hereditary loss-of-function mutation in one human Na+ channel isoform - NaV1.7 - with a rare genetic disorder known as Congenital Insensitivity to Pain (CIP). Individuals with CIP have reduced sensitivity to normally painful stimuli without significant deficits to sensory or cognitive function. A compellin body of evidence indicates that selective inhibition of NaV1.7 in normal humans couldrecapitulate the phenotype of CIP. The high homology of human NaV proteins, coupled with challenges associated with high-throughput screening against multiple ion channel targets, have thwarted most efforts to develop selective antagonists for individualNaV subtypes. Recent findings indicate that a two amino acid variation in the pore region of hNaV1.7 is responsible for reduced potency of a family of naturally-occurring sodium channel antagonists, the guanidinium toxins (GTxs), against this isoform. Thisvariation is present in all known hNaV1.7 splice variants, but is not found in any other human NaV isoform. Computational modeling studies and protein mutagenesis experiments indicate that it may be possible to restore potency of the GTxs against hNaV1.7while destabilizing GTx binding to the other eight hNaV isoforms by judicious synthetic modifications. A plan is in place to prepare analogues of the GTxs designed to bind with high affinity to hNaV1.7, and to test these compounds by whole-cell electrophysiology to measure potency and isoform-selectivity. Success of this program will provide 1) an improved understanding of the NaV pore structure and GTx binding pose, 2) a novel tool to validate NaV1.7 as a target for pain treatment, and 3) a high-affinity,isoform-selective sodium channel antagonist as a lead compound for optimization toward a next-generation pain therapeutic. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Existing paradigms for the treatment of moderate-to-severe pain rely heavily on prescription narcotics, such as morphine, oxycodone and fentanyl, which affect the central nervous system and are associated with a range of side effects including nausea, drowsiness, respiratory depression and potential for addiction. We aim to develop a next-generation pain therapy that specifically targets pain signals without affecting cognition. Such a therapy is expected to show improved efficacy and significantly fewer/milder side effects than existing drugs.

* Information listed above is at the time of submission. *

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