TWIK-related K+ (TREK) channels are potential analgesic targets. However, selective activators for TREK with both defined action mechanism and analgesic ability for chronic pain have been lacking. Here we report C3001a, a selective activator for TREK against other two-pore domain K+ (K2P) channels. C3001a binds to the cryptic binding site formed by P1 and TM4 in TREK-1, as suggested by computational modeling and experimental analysis. Further, we identify the carboxyl group of C3001a as a structural determinant for the binding to TREK-1/2, and the key residue that defines the subtype-selectivity of C3001a. C3001a targets TREK channels in peripheral nervous system to reduce the excitability of nociceptive neurons. In neuropathic pain, C3001a alleviated spontaneous pain and cold hyperalgesia. In a mouse model of acute pancreatitis, C3001a alleviated mechanical allodynia and inflammation. Together, C3001a represents a lead compound which could advance the rational design of peripherally-acting analgesics targeting K2P channels without opioid-like adverse effects.
Effects of multicomponent primary care-based intervention on immunization rates and missed opportunities to vaccinate adults.
March 5, 2020
- ACC 2020The American College of Cardiology decided to cancel ACC.20/WCC due to COVID-19, which was scheduled to take place March 28-30 in Chicago. However, ACC.20/WCC Virtual Meeting continues to release cutting edge science and practice changing updates for cardiovascular professionals on demand and free through June 2020.
- ENDO: 2020ENDO 2020 Annual Conference has been canceled due to COVID-19. Here are highlights of emerging data that has still been released. Keep an eye out for ENDO Online 2020, which will take place from June 8 to 22.
- Psych Congress 2019The annual Psych Congress, held in San Diego, California, from October 3-6, 2019, brings together members of the entire mental health team, including psychiatrists, physician assistants, nurse practitioners, psychologists, and primary care physicians, with experts in mental health to improve patient outcomes through education.