| Abstract No.: | 300 |
| Country: | Canada |
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| Title: | Translational Biomedical Research: The Development of Calcium Channel Antagonists for Pain Intervention |
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| Authors/Affiliations: | Terry Snutch,
University of British Columbia, Vancouver, BC, Canada |
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| Content: | Voltage-gated calcium (Ca) channels are implicated in a number of human pathophysiological conditions and are strong candidates as therapeutic targets for pain intervention. In one instance, high voltage-activated N-type Ca channels N-type play a crucial role in mediating nociceptive neurotransmission in primary afferents with terminals in the dorsal horn of the spinal cord. We have previously designed and developed novel classes of orally available N-type Ca channel blockers and advanced these through into human clinical trials. Distinct from N-type channels, low voltage-activated T-type Ca channels play crucial roles in mediating neuronal firing patterns and bursting behaviors. Three genes encoding mammalian T-type channels that exhibit distinct regional distributions and biophysical properties have been described (CaV3.1, CaV3.2 and CaV3.3). Related to pain transmission, T-type calcium currents are found in a subset of small and medium diameter primary afferent neurons as well as interneurons from the superficial laminae of the dorsal horn. Data will be presented on the development of a unique high-throughput fluorescent assay for T-type Ca channel blockers. Combining this cell-based assay with a rationale drug structure-activity approach, we have identified novel, high affinity and selective T-type Ca blockers aimed at targeting peripheral and central pain processing pathways. |
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