The melanocortin system is involved in the regulation of several complex physiological functions. In particular, the melanocortin-3 and -4 receptors (MC3R/MC4R) have been demonstrated to regulate body weight, energy homeostasis, and feeding behavior. Synthetic and endogenous melanocortin agonists have been shown to be anorexigenic in rodent models. Herein, we report synthesis and structure-activity relationship (SAR) studies of 27 nonpeptide small molecule ligands based on an unsymmetrical substituted urea core. Three templates containing key residues from the lead compounds, showing diversity at three positions (R1, R2, R3), were designed and synthesized. The syntheses were optimized for efficient microwave-assisted chemistry that significantly reduced total syntheses time compared to a previously reported room temperature method. The pharmacological characterization of the compounds on the mouse melanocortin receptors identified compounds 1 and 12 with full agonist activity at the mMC4R, but no activity was observed at the mMC3R when tested up to 100 μM concentrations. The SAR identified compounds possessing aliphatic or saturated cyclic amines at the R1 position, bulky aromatic groups at the R2 position, and benzyl group at the R3 position resulted in mMC4R selectivity over the mMC3R. The small molecule template and SAR knowledge from this series may be helpful in further design of MC3R/MC4R selective small molecule ligands.
Bibliographical noteFunding Information:
This work has been supported by NIH Grant R01DK091906 (C.H.-L.).A.S. and C.H.-L. designed the research. A.S., J.K., M.L.S.D. and H.H performed the experiments. A.S. and C.H.-L. analyzed the data. A.S. wrote the manuscript with the help of C.H.-L.
- Melanocortin receptors
- melanocortin agonist
- melanocortin-3 receptor
- melanocortin-4 receptor
- small molecules
- urea ligands