Selective Inhibition of Adenylyl Cyclase 1 for the Treatment of Chronic Pain

The opioid epidemic has reached new highs in the past decade, with opioid overdose becoming the leading cause of death for Americans age 18-45 in 2019. While there is ongoing research into novel opioids that may avoid the development of tolerance and addiction, there is also research into alternative targets downstream of the opioid receptor. Adenylyl cyclase type 1 (AC1) is one such downstream effector of the opioid receptors that is crucial for opioid-based analgesia. By selectively targeting AC1, bypassing the opioid receptor, we may avoid the development of tolerance and addiction seen with opioid therapy while still treating chronic pain. In this report we have optimized a novel scaffold of selective AC1 inhibitors, the pyrimidinones.Through two generations of pyrimidinones analogs we have yielded the lead compound AC10084, an AC1 inhibitor as efficacious as morphine in vivo with improved aqueous solubility relative to previous AC1 inhibitor scaffolds. Furthermore, utilizing our pyrimidinone scaffold in a pharmacophore-based virtual screen has yielded yet another novel scaffold of AC1 inhibitors, the dithiophenes. In total, our highly collaborative project provides strong evidence that AC1 can be selectively targeted for chronic pain management and that AC1 inhibitors may represent a future alternative for traditional opioids.