Research ArticlePharmacology

Identification of a selective small-molecule inhibitor of type 1 adenylyl cyclase activity with analgesic properties

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Sci. Signal.  21 Feb 2017:
Vol. 10, Issue 467, eaah5381
DOI: 10.1126/scisignal.aah5381

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Pain relief through AC1 inhibition

Brust et al. identified a small-molecule inhibitor of adenylyl cyclase 1 (AC1), which is a potential target for treating pain and reducing the dependency on opioids for pain management. The challenge has been that there are many AC isoforms and their function is crucial to most physiological processes, so isoform specificity is key to any chance of therapeutic efficacy. The authors identified two compounds that inhibited AC1 in a screen of a chemical library of natural compounds that reduced the production of adenosine 3′,5′-monophosphate (cAMP), the product of AC activity. One of the compounds, ST034307, showed selective inhibition of AC1 over all eight other AC isoforms. This compound produced analgesia in a mouse model of inflammatory pain, blocked cellular changes associated with opioid dependency in transfected cells, and inhibited cAMP accumulation in both transfected cells and hippocampal tissue samples. This compound should not only be a useful tool for investigating AC1-specific physiology but also provide support for the development of AC1-selective pain relievers.