Abstract | BACKGROUND:
Voltage-gated sodium channels (Na(v)1) are expressed in primary sensory neurons where they influence excitability via their role in the generation and propagation of action potentials. Recently, human genetic data have shown that one sodium channel subtype, Na(v)1.7, plays a major role in pain. We performed these studies to characterize the antinociceptive effects of N-[(R)-1-((R)-7-chloro-1-isopropyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-ylcarbamoyl)-2-(2-fluorophenyl)-ethyl]-4-fluoro-2-trifluoromethyl- benzamide (BZP), a non-central nervous system (CNS) penetrant small molecule with high affinity and preferential selectivity for Na(v)1.7 over Na(v)1.8 and Na(v)1.5. METHODS: BZP was evaluated in rat preclinical models of inflammatory and neuropathic pain and compared with standard analgesics. Two models were used: the complete Freund's adjuvant model of inflammatory pain and the spinal nerve ligation model of neuropathic pain. BZP was also evaluated in a motor coordination assay to assess its propensity for CNS side effects. RESULTS: CONCLUSIONS: These data suggest that a peripherally acting sodium channel blocker, preferentially acting through Na(v)1.7, could provide clinical relief of chronic pain without the CNS side effects typical of many existing pain treatments.
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Authors | Erin McGowan, Scott B Hoyt, Xiaohua Li, Kathryn A Lyons, Catherine Abbadie |
Journal | Anesthesia and analgesia
(Anesth Analg)
Vol. 109
Issue 3
Pg. 951-8
(Sep 2009)
ISSN: 1526-7598 [Electronic] United States |
PMID | 19690272
(Publication Type: Journal Article)
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Chemical References |
- Analgesics
- Benzamides
- N-((R)-1-((R)-7-chloro-1-isopropyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo(b)azepin-3-ylcarbamoyl)-2-(2-fluorophenyl)ethyl)-4-fluoro-2-trifluoromethyl-benzamide
- NAV1.7 Voltage-Gated Sodium Channel
- Scn9a protein, rat
- Sodium Channels
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Topics |
- Analgesics
(pharmacology)
- Animals
- Benzamides
(pharmacology)
- Cell Line
- Humans
- Hyperalgesia
(pathology)
- Inflammation
- Male
- NAV1.7 Voltage-Gated Sodium Channel
- Nerve Degeneration
(pathology)
- Pain
- Rats
- Rats, Sprague-Dawley
- Sodium Channels
(metabolism)
- Spinal Nerves
(pathology)
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