Optimization of a 1,3,4-oxadiazole series for inhibition of Ca2þ/ calmodulin-stimulated activity of adenylyl cyclases 1 and 8 for the treatment of chronic pain
Adenylyl cyclases type 1 (AC1) and 8 (AC8) are group 1 transmembrane adenylyl cyclases (AC) that are stimulated by Ca2þ/calmodulin. Studies have shown that mice depleted of AC1 have attenuated inflammatory pain response, while AC1/AC8 double-knockout mice display both attenuated pain response and opioid dependence. Thus, AC1 has emerged as a promising new target for treating chronic pain and opioid abuse. We discovered that the 1,3,4-oxadiazole scaffold inhibits Ca2þ/calmodulin-stimulated cyclic adenosine 3‘,5‘-monophosphate (cAMP) production in cells stably expressing either AC1 or AC8. We then carried out structure-activity relationship studies, in which we designed and synthesized 65 analogs, to modulate potency and selectivity versus each AC isoform in cells. Furthermore, molecular docking of the analogs into an AC1 homology model suggests the molecules may bind at the ATP binding site. Finally, a prioritized analog was tested in a mouse model of inflammatory pain and exhibited modest analgesic properties. In summary, our data indicate the 1,3,4-oxadiazoles represent a novel scaffold for the cellular inhibition of Ca2þ/calmodulin-stimulated AC1- and AC8 cAMP and warrant further exploration as potential lead compounds for the treatment of chronic inflammatory pain.