HYP-1, a novel diamide compound, relieves inflammatory and neuropathic pain in rats.

Abstract

In the present study, we investigated whether a novel compound, 2-(2-(4-((4-chlorophenyl)(phenyl)methyl) piperazin-1-yl)-2-oxoethylamino)-N-(3,4,5-trimethoxybenzyl)acetamide (HYP-1), is capable of binding to voltage-gated sodium channels (VGSCs) and evaluated both its inhibitory effect on Na+ currents of the rat dorsal root ganglia (DRG) sensory neuron and its in vivo analgesic activity using rat models of inflammatory and neuropathic pain. HYP-1 showed not only high affinity for rat sodium channel (site 2), but also potent inhibitory activity against the TTX-R Na+ currents of the rat DRG sensory neuron. HYP-1 co-injected with formalin (5%, 50 μl) under the plantar surface of rat hind paw dose-dependently reduced spontaneous pain behaviors during both the early and late phases. This result was confirmed by c-Fos immunofluorescence in the L4-5 spinal segments. A large number of c-Fos-positive neurons were observed in rat injected with a mixture of formalin and vehicle, but not in rat treated with a mixture of formalin and HYP-1. In addition, the effectiveness of HYP-1 (6 and 60 mg/kg, i.p.) in suppression of neuropathic pain, such as mechanical, cold and warm allodynia, induced by rat tail nerve injury was investigated. HYP-1 showed limited selectivity over hERG, N-type and T-type channels.Our present results indicate that HYP-1, as a VGSC blocker, has potential analgesic activities against nociceptive, inflammatory and neuropathic pain.

• Authors: Yoo Lim Kam, Seung Keun Back, Bohee Kang, Young-Yun Kim, Hwa-Jung Kim, Hyewhon Rhim, Seung-Yeol Nah, Jun-mo Chung, Dong Hyun Kim, Jin-Sung Choi, Heung Sik Na, Hea-Young Park Choo
• Journal: Pharmacology, biochemistry, and behavior (Pharmacol Biochem Behav) Vol. 103 Issue 1 Pg. 33-42 (Nov 2012) ISSN: 1873-5177 [Electronic] United States
• PMID: 22867799 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-(2-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)-2-oxoethylamino)-N-(3,4,5-trimethoxybenzyl)acetamide
• Acetamides
• Analgesics, Non-Narcotic
• Anti-Inflammatory Agents, Non-Steroidal
• Proto-Oncogene Proteins c-fos
• Voltage-Gated Sodium Channel Blockers
• Voltage-Gated Sodium Channels

Topics

• Acetamides (chemical synthesis, pharmacology)
• Analgesics, Non-Narcotic (chemical synthesis, pharmacology)
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (chemical synthesis, pharmacology)
• Ganglia, Spinal (drug effects, metabolism)
• HEK293 Cells
• Humans
• Hyperalgesia (drug therapy, physiopathology)
• Inflammation (drug therapy)
• Male
• Neuralgia (drug therapy, physiopathology)
• Pain Measurement
• Patch-Clamp Techniques
• Proto-Oncogene Proteins c-fos (metabolism)
• Rats
• Rats, Sprague-Dawley
• Sensory Receptor Cells (drug effects, metabolism)
• Voltage-Gated Sodium Channel Blockers (chemical synthesis, pharmacology)
• Voltage-Gated Sodium Channels (metabolism)