Based on the aforementioned in vivo genetic data, a key requirement for a suitable AC1 modulator for chronic pain therapy is that it must be selective for AC1 versus AC8 to avoid the potential for memory impairment. Our group and others have since screened and tested for such modulators; the resultant known AC1 inhibitors and modulators include the adenosine-based SQ22536, the adenosine-based NB001, the chromone ST034307, and the oxadiazole AC10065 (Figure ). However, each molecule presents drawbacks and challenges for potential use as a pharmacotherapeutic agent. SQ22536 is proposed to bind the catalytic site of AC, and while it displays cellular potency of >10 µM (IC50) versus AC1 it lacks selectivity versus other isoforms including AC5. NB001 likewise has only 14-fold selectivity for AC1 versus AC8 in cell-based assays. Given that both of these compounds have adenine moieties, there is concern for selectivity versus other adenine-binding and ATP-binding proteins that could lead to off-target effects in vivo. Our group previously published the chromone ST034307, which has a 2.3 µM IC50 versus Ca 2+ /CaM-stimulated AC1 activity in cells with no inhibition of AC8. This selective modulator was then shown to produce analgesic effects versus inflammatory pain in vivo. Despite this activity, the molecule presented significant physicochemical liabilities, namely poor aqueous solubility which hampered dosing. Furthermore, SAR was found to be intractable beyond the published data. In the interest of finding a scaffold with tractable SAR and better drug-like characteristics, a high-throughput screen was undertaken followed by SAR elucidation of the oxadiazole series, yielding the most recent AC1 modulator AC10065. This compound inhibited AC1-mediated Ca 2+ /CaM-stimulated cAMP production in cells with an IC50 of 1.4 µM versus AC1 and 4.1 µM versus AC8, and displayed modest in vivo efficacy in a mouse CFA inflammatory pain model. However, the oxadiazole series was once again limited in dosing due to the scaffold's poor aqueous solubility. In summation, these current AC1 modulators suggest that AC1 inhibition can produce anti-allodynic effects in behavioral animal studies and that isoform selectivity between AC1 and AC8 is achievable.