Morphine is widely used for the treatment of severe pain. This analgesic effect is mediated principally by the activation of μ-opioid receptors (MOR). However， prolonged activation of MOR also results in tolerance， dependence， addiction， constipation， nausea， sedation， and respiratory depression. To address this problem， we sought alternative ways to activate MOR - either by use of novel ligands， or via a novel activation mechanism. To this end， a series of compounds were screened using a sensitive CHO-K1/MOR/Gα15 cell-based FLIPR calcium high-throughput screening (HTS) assay， and the bithiazole compound 5a was identified as being able activate MOR in combination with naloxone. Structura... More
Morphine is widely used for the treatment of severe pain. This analgesic effect is mediated principally by the activation of μ-opioid receptors (MOR). However， prolonged activation of MOR also results in tolerance， dependence， addiction， constipation， nausea， sedation， and respiratory depression. To address this problem， we sought alternative ways to activate MOR - either by use of novel ligands， or via a novel activation mechanism. To this end， a series of compounds were screened using a sensitive CHO-K1/MOR/Gα15 cell-based FLIPR calcium high-throughput screening (HTS) assay， and the bithiazole compound 5a was identified as being able activate MOR in combination with naloxone. Structural modifications of 5a resulted in the discovery of lead compound 5j， which could effectively activate MOR in combination with the MOR antagonist naloxone or naltrexone. In vivo， naloxone in combination with 100?mg/kg of compound 5j elicited antinociception in a mouse tail-flick model with an ED of 17.5?±?4?mg/kg. These results strongly suggest that the mechanism by which the 5j/naloxone combination activates MOR is worthy of further study， as its discovery has the potential to yield an entirely novel class of analgesics.
