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.
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
Posted by
Jatinder Kaur
on 12 09 2019
Related content
03 10 2022
< 1 minute
Calculate on the cloud
In order to increase the flexibility, access and integrability, Calculators and Predictors have...
12 05 2022
< 1 minute
Coupling stabilizers open KV1-type potassium channels
ABSTRACT: The opening and closing of voltage-gated ion channels are regulated by voltage sensors...
13 11 2021
< 1 minute
Cheminfo Stories 2021 Virtual UGM | Boost analytical experiments with phys-chem properties
TRY CHEMICALIZE Log in for videos & slides
13 11 2021
< 1 minute
Cheminfo Stories 2021 Virtual UGM | Enhancing Sibylla’s innovative drug discovery platform with ChemAxon
Sibylla's innovative pharmacological platform is aimed at discovering new drugs for untreatable...