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Our current portfolio of medicinal chemistry projects includes the development of probe compounds and drug candidates for neuroscience applications. We have discovered five novel classes of opioids, including three agonists and two antagonists, with potencies of at least 1 µM and 100-fold selectivity for the kappa opioid receptor (KOR) over delta (DOR) and mu (MOR). Our current efforts focus on developing G-protein biased agonists of the kappa opioid receptor (KOR) in collaboration with Laura Bohn (Scripps), Sara Jones and Jeff Martin (Wake Forest). Biased activation of the kappa opioid receptor has shown promise in delivering desirable antinociceptive effects with reduced side effects, like sedation seen with “balanced” KOR agonists, and a reduced risk of addiction. Our efforts to develop such agents designed to shed light on the intracellular signaling pathways of the KOR allow us to evaluate these pathways as targets for new drugs for addiction and depression.
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Triazole 1.1

GTPγS EC50 = 31 nM 

βArrestin EC50 = 4129 nM

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Bisamide ML139

GTPγS EC50 = 6.7 nM

βArrestin EC50 = 111.3 nM

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Isoquinolinone 2.1

GTPγS EC50 = 84.7 nM 

βArrestin EC50 = >10,000 nM

In addition, the group is interested in other neurochemistry projects. We have discovered several novel sigma-1 binders and published a series of probes as dopamine modulators in collaboration with Kevin Frankowski (UNC Chapel Hill) and David Sibley (NINDS). We are also interested in neurodegenerative diseases such as the search for inhibitors for new modalities for Huntington’s Disease in collaboration with Nancy Muma (University of Kansas) and accelerating the discovery of innovative medicines to treat Angelman syndrome in collaboration with Ben Philpot (UNC Chapel Hill)
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