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Scientists propose to create a novel painkiller with no adverse effects on body temperature
Antagonists (blockers) of the so-called TRPV1 channel are being developed as novel painkillers by several pharmaceutical companies. This development, however, has been hindered by adverse effects on body temperature – some TRPV1 antagonists increase body temperature (cause hyperthermia), whereas others decrease it (cause hypothermia). The research team at Dignity Health St. Joseph’s Hospital and Medical Center (Phoenix, AZ), headed by Professor Andrej Romanovsky, M.D., Ph.D., collaborated with scientists at AbbVie (North Chicago, IL), Amgen (Thousand Oaks, CA), and the Medical School at the University of Pécs (Pécs, Hungary) to address this problem.
This international team of academic scientists and pharma researchers has found that the different adverse effects on body temperature stem from the same mechanism. If this mechanism is tamed, the drug will not affect body temperature in either direction. This research has been recently published in the journal Acta Physiologica. http://onlinelibrary.wiley.com/doi/10.1111/apha.13038/full
For more than 10 years, Dr. Romanovsky’s laboratory has studied TRPV1 antagonists, synthesized by different pharmaceutical companies, each having a different effect on body temperature. "Until now," says Andras Garami, M.D., Ph.D., an early participant in this work and the first author on the Acta Physiologica paper, "we thought that different effects of TRPV1 antagonists on body temperature were caused by different mechanisms. To our surprise," continues Dr. Garami, "the present study shows that the hyperthermic and hypothermic effects are in fact caused through a reverse modulation of the exact same mechanism!" "The TRPV1 channel can be activated by different agents," explains Dr. Romanovsky, "but only one type of channel activation affects what will happen to the body temperature. It is the activation by an acidic environment. If an antagonist blocks this activation, hyperthermia occurs; if it exaggerates it, then hypothermia develops." This discovery paves the way for creating new TRPV1 antagonists with no side effects: in order to have no temperature effects, the new compounds should not interfere with TRPV1 activation by an acidic environment.
"Understanding how the pharmacological profile of a TRPV1 antagonist affects body temperature is also important for repurposing TRPV1 antagonists,” says William Schmidt, Ph.D., President and CEO of Catalina Pharma, one of the startups working on new medical uses for these compounds. “Many pharmaceutical companies tried to develop TRPV1 antagonists, and even studied them in early-stage clinical trials," continues Dr. Schmidt, “but, due to their adverse effects on body temperature, the development of most compounds was terminated. Now, they are sitting on the shelf, so to speak, and waiting for potential new uses. Better understandings of how the pharmacological profile of compounds are linked to effects on the body temperature – and this is what the paper gives us – is of enormous help."