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. Agonists that can stimulate one pathway and avoid another downstream of receptor engagement are referred to as biased agonists. We have developed several selective biased agonists designed to activate MOR-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. Unpublished work examining the chronic administration of these compounds will also be presented.

Evaluation of opioid antinociceptive tolerance with G-protein signaling biased opioid agonists

256th National Meeting (2018)

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