Selective Adenylyl Cyclase Type 1 Inhibitors as Potential Opioid Alternatives For Chronic Pain

Chronic pain is a major health concern that costs the US more than $635 billion per year (Gaskin and Richard, 2012). The drugs used for the management of chronic pain include opioid analgesics, neuronal stabilizers such as anticonvulsants, and antidepressants. Opioids are the most widely used analgesics; however, there are significant problems associated with long-term opioid therapy for chronic pain, including diversion and addiction (Volkow and McLellan, 2016). Moreover, the pharmaceutical industry has retreated from studying novel pain therapeutics due to the enormous risk and low probability of success that reflect in part, a lack of predictive animal models and biomarkers (Skolnick and Volkow, 2016). These observations indicate an essential need for academic investigators to identify new agents acting on unique targets in the war on chronic pain. Neurobiological, genetic, and preclinical studies have implicated neuronal adenylyl cyclase type 1 (AC1) as a potential new target (Zhuo, 2012). Adenylyl cyclases (AC) are members of an enzyme family that serve as effectors for numerous G-protein-coupled receptors (for example, opioid receptors) and produce the second messenger cAMP from ATP. The nine membrane-bound isoforms of AC share a similar structure and each is uniquely regulated by G protein subunits, Ca²⁺, protein kinases, and subcellular localization (Dessauer et al, 2017). Membrane-bound ACs are highly expressed in the central nervous system and generally have overlapping expression patterns. Animals lacking one or multiple AC isoforms have been essential tools to inform on the physiological roles of AC signaling in the central nervous system.

AC1 and AC8 are robustly activated by Ca²⁺/calmodulin (Ca²⁺/CaM) and have overlapping expression patterns in neuronal tissues, including the hippocampus and several cortical regions (Dessauer et al, 2017). Studies with mice lacking either AC1 (AC1^−/−), AC8 (AC8^−/−), or both isoforms (double knockout mice, DKO) revealed that AC1 and AC8 are not required for acute pain responses; however, the behavioral responses to inflammatory stimuli (that is, formalin and CFA) were nearly eliminated or abolished in AC1^−/− or DKO mice, respectively (Zhuo, 2012). Unfortunately, the DKO mice showed significant memory deficits, making it imperative to find agents that selectively target AC1. Dr Zhuo and colleagues identified the first selective small molecule inhibitor of AC1, NB001, and demonstrated efficacy in multiple chronic pain models in both mice and rats (Wang et al, 2011). NB001 has modest (14-fold) selectivity for AC1 vs the closely-related AC8 isoform and had activity consistent with AC1 inhibition in neuronal cells and tissues (Wang et al, 2011). We recently screened a small (3040 compounds) natural product-like chemical library and identified an additional small molecule that selectively inhibited AC1, ST034307 (Brust et al, 2017). ST034307 is a small chromone derivative with unprecedented selectivity for inhibiting AC1 vs the other AC isoforms. The precise site of AC1 engagement is unknown; however, ST034307 appears to have a mechanism of action that is unique from other known AC inhibitors. It was shown to dose-dependently reduce opioid dependence in a cellular model and inhibited allodynia in a phenotypic mouse model of inflammatory pain (Brust et al, 2017). These data support the development of additional selective AC1 inhibitors for the treatment of chronic pain conditions as potential alternatives to opioids.

Funding and disclosure

The work was supported in part by NIH MH101673 and Purdue University. The author declares no conflict of interest.