A potent and selective nonpeptide antagonist of the melanocortin-4 receptor induces food intake in satiated mice.

@article{Pontillo2005APA,
  title={A potent and selective nonpeptide antagonist of the melanocortin-4 receptor induces food intake in satiated mice.},
  author={Joseph Pontillo and Joseph A Tran and Stacy Markison and Margaret Joppa and Beth A Fleck and Dragan Marinkovi{\'c} and Melissa Arellano and Fabio C. Tucci and Marion C Lanier and Jodie Nelson and John Saunders and Samuel R J Hoare and Alan C. Foster and Chen Chen},
  journal={Bioorganic & medicinal chemistry letters},
  year={2005},
  volume={15 10},
  pages={2541-6}
}
Optimization on a series of piperazinebenzylamines resulted in analogues with low nanomolar binding at the human MC4 receptor but weak affinity (Ki > 500 nM) at the MC3 receptor. Compound 14c was identified to be a potent MC4R antagonist (Ki = 3.2 nM) with a selectivity of 240-fold over MC3R. It proved to be an insurmountable antagonist in a cAMP assay. Compound 14c potently stimulated food intake in satiated mice when given by intracerebroventricular administration.