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

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Molecular Biology

Background:

• The calcitonin (CT) receptor and its peptide agonists are validated drug targets.
• A previously identified small molecule agonist, SUN-B8155, activates the CT receptor (CTR).
• Understanding structure-activity relationships is crucial for developing novel therapeutics.

Purpose of the Study:

• To synthesize and characterize novel CTR agonists derived from SUN-B8155.
• To investigate the structure-activity relationships, signaling bias, and cellular activity of these new compounds.
• To evaluate the potential of these compounds in inhibiting tumor cell invasion.

Main Methods:

• Synthesis of a series of nine novel compounds (S8155 1-9) based on the SUN-B8155 scaffold.
• Assessment of G protein activity and receptor affinity.
• Evaluation of β-arrestin-2 signaling bias and cellular activity, including inhibition of tumor cell invasion.

Main Results:

• The N-hydroxyl group on the pyridone ring is essential for G protein activity and CT receptor affinity.
• Compound S8155-7 demonstrated enhanced G protein activity.
• Compound S8155-4 exhibited a significant β-arrestin-2 signaling bias.
• Both S8155-4 and S8155-7 effectively inhibited tumor cell invasion through CTR activation.

Conclusions:

• Novel calcitonin receptor agonists with distinct signaling profiles have been developed.
• Specific structural modifications influence G protein activity and β-arrestin signaling.
• Compounds S8155-4 and S8155-7 show promise for chemical biology research and drug development targeting the CT receptor, particularly for inhibiting tumor cell invasion.