Optimization of a 1,3,4-oxadiazole series for inhibition of Ca²⁺/calmodulin-stimulated activity of adenylyl cyclases 1 and 8 for the treatment of chronic pain.

ABSTRACT: Adenylyl cyclases type 1 (AC1) and 8 (AC8) are group 1 transmembrane adenylyl cyclases (AC) that are stimulated by Ca²⁺/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 Ca²⁺/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. Furt

SUBMITTER: Kaur J 

PROVIDER: S-EPMC6310635 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature