GPCRs can signal via multiple pathways and in the endogenous environment, these pathways may vary depending on where the receptor is expressed. The key challenge is to determine how receptors function in vivo to mediate diverse physiologies, depending on where they are located, and how they signal. Early genetic knockout studies support a hypothesis that an agonist that promotes mu opioid receptor (MOR) coupling to G protein pathways without beta-arrestin2 recruitment might be a way to promote antinociception while limiting the side effects associated with opiate narcotic analgesics. Therefore, we have developed several selective MOR biased agonists designed to activate G protein signaling pathways over beta-arrestin2 pathways and have investigated whether divergent signaling in vitro can predict divergent physiologies in mouse models of opioid responsiveness. Our studies show that for such compounds, G protein signaling is preserved in vivo as well as the antinociceptive properties in mice. However, respiratory suppression is greatly attenuated. A correlation between calculated bias factors, used for ranking compound selection, and the widening of the therapeutic window in vivo will be discussed.

Biasing opioid receptor signaling away from opiate side effects

254th National Meeting (2017)

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