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.

Abstract

Adenylyl cyclase 1 (AC1) belongs to a group of adenylyl cyclases (ACs) that are stimulated by calcium in a calmodulin-dependent manner. Studies with AC1 knockout mice suggest that inhibitors of AC1 may be useful for treating pain and opioid dependence. However, nonselective inhibition of AC isoforms could result in substantial adverse effects. We used chemical library screening to identify a selective AC1 inhibitor with a chromone core structure that may represent a new analgesic agent. After demonstrating that the compound (ST034307) inhibited Ca2+-stimulated adenosine 3′,5′-monophosphate (cAMP) accumulation in human embryonic kidney (HEK) cells stably transfected with AC1 (HEK-AC1 cells), we confirmed selectivity for AC1 by testing against all isoforms of membrane-bound ACs. ST034307 also inhibited AC1 activity stimulated by forskolin- and Gαs-coupled receptors in HEK-AC1 cells and showed inhibitory activity in multiple AC1-containing membrane preparations and mouse hippocampal homogenates. ST034307 enhanced μ-opioid receptor (MOR)–mediated inhibition of AC1 in short-term inhibition assays in HEK-AC1 cells stably transfected with MOR; however, the compound blocked heterologous sensitization of AC1 caused by chronic MOR activation in these cells. ST034307 reduced pain responses in a mouse model of inflammatory pain. Our data indicate that ST034307 is a selective small-molecule inhibitor of AC1 and suggest that selective AC1 inhibitors may be useful for managing pain.

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