Cell active and functionally-relevant small-molecule agonists of calcitonin receptor

The natural calcitonin (CT) receptor and its peptide agonists are considered validated targets for drug discovery. A small molecule agonist, SUN-B8155, has previously been shown to efficiently activate cellular CTR. Herein, we report the synthesis of a series of compounds (S8155 1-9) derived from SUN-B8155, and investigate the structural-functional relationship, bias properties and their cellular activity profile. We discover that the N-hydroxyl group from the pyridone ring is required for G protein activity and its affinity to the CT receptor. Among the compounds studied, S8155-7 exhibits improved G protein activity while S8155-4 displays a significant beta-arrestin-2 signaling bias. Finally, we show that both S8155-4 and S8155-7 inhibit tumour cell invasion through CTR activation. These two compounds are anticipated to find extensive applications in chemical biology research as well drug development efforts targeting CT receptor.