Structure–Activity Relationship Studies of the Natural Product Gq/11Protein Inhibitor YM‐254890

G proteins act as molecular switches in G protein-coupled receptor signaling pathways and are key mediators for numerous important physiological processes. The natural product, cyclic depsipeptide YM-254890, together with the structurally similar FR900359, is the only known selective inhibitor of the Gq/11 subfamily of G proteins. We recently reported the first total synthesis of YM-254890 and FR900359, followed by synthesizing analogues to perform structure-activity relationship studies. However, incomplete information about their structure-activity relationship prevents the further development of potent and structurally simplified analogues. Herein we report the first systematic structure-activity relationship study toward the N-methyldehydroalanine moiety in YM-254890, by designing and synthesizing seven new analogues. Pharmacological characterization of the seven compounds for Gq/11 -, Gi/o - and Gs -mediated signaling showed that the simplified analogue YM-19 is the most potent Gq/11 inhibitor among the new analogues. This study provides information for the future design of potent and simplified YM-254890 analogues.