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Analogs of α-melanocyte stimulating hormone with high agonist potency and selectivity at human melanocortin receptor 1b: The role of Trp9 in molecular recognition†

  1. Maria A. Bednarek1,*,
  2. Tanya MacNeil2,
  3. Rui Tang2,
  4. Tung M. Fong2,
  5. M. Angeles Cabello3,
  6. Marta Maroto3,
  7. Ana Teran3

Article first published online: 9 OCT 2007

DOI: 10.1002/bip.20863

Issue

Biopolymers

Biopolymers

Special Issue: This issue is dedicated to the memory of Elkan R. Blout, a founding editor of Biopolymers

Volume 89, Issue 5, pages 401–408, May 2008

Additional Information

How to Cite

Bednarek, M. A., MacNeil, T., Tang, R., Fong, T. M., Angeles Cabello, M., Maroto, M. and Teran, A. (2008), Analogs of α-melanocyte stimulating hormone with high agonist potency and selectivity at human melanocortin receptor 1b: The role of Trp9 in molecular recognition. Biopolymers, 89: 401–408. doi: 10.1002/bip.20863

Author Information

  1. 1

    Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ

  2. 2

    Department of Obesity and Metabolic Disorders, Merck Research Laboratories, Rahway, NJ

  3. 3

    Centro de Investigacion Basica, Merck Sharp and Dohme de Espana, S.A., Madrid, Spain

*Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ

  1. †

    Dedicated to the memory of Dr. Elkan R. Blout in whose lab, at Harvard Medical School, I (M.A. Bednarek) had the privilege to work in the early eighties. At that time Prof. E. R. Blout (frequently called ERB by his coworkers) had numerous responsibilities as a Professor at Harvard Medical School, and also as Dean of Academic Affairs at the Harvard School of Public Health and Treasurer at the National Academy of Sciences. Every week for a half an hour, however, he gave undivided attention to each member of his laboratory, his postdoctoral students and visiting scientists. We all looked forward to those brief but so rewarding interactions. He expected us to be independent scientists, concise and clear about what we wanted to accomplish. He discussed our efforts and judgments, provided criticism and reassurance. And all the time we were absolutely in awe of this brilliant scientist, teacher, mentor, manager, statesman and businessman. He was our rock, always calm, friendly, and kind. We felt very fortunate to be part of ERB's world, participate in his research endeavors, and observe his extraordinary interactions with scientists, managers, business people and politicians. It was certainly a unique experience reaching far beyond the typical postdoctoral training. I treasure memories of Dr. Elkan R. Blout from the lab at Harvard Medical School. Equally warmly, I treasure memories of ERB and his family from the lab gatherings at the Harvard and Commonwealth Clubs or at his house.

Publication History

  1. Issue published online: 28 FEB 2008
  2. Article first published online: 9 OCT 2007
  3. Manuscript Accepted: 28 SEP 2007
  4. Manuscript Revised: 17 SEP 2007
  5. Manuscript Received: 25 JUN 2007

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Keywords:

  • melanotropins;
  • melanocortin receptor 1;
  • MC1R;
  • agonist;
  • binding affinity assay;
  • cAMP accumulation assay

Abstract

α-Melanocyte stimulating hormone (αMSH), Ac-Ser1-Tyr2-Ser3-Met4-Glu5-His6-Phe7-Arg8-Trp9-Gly10-Lys11-Pro12-Val13-NH2, is an endogenous agonist for the melanocortin receptor 1 (MC1R), the receptor found in the skin, several types of immune cells, and other peripheral sites. Three-dimensional models of complexes of this receptor with αMSH and its synthetic analog NDP-αMSH, Ac-Ser1-Tyr2-Ser3-Nle4-Glu5-His6-D-Phe7-Arg8-Trp9-Gly10-Lys11-Pro12-Val13-NH2, have been previously proposed. In those models, the 6–9 segment of the ligand was considered essential for the ligand-receptor interactions. In this study, we probed the role of Trp9 of NDP-αMSH in interactions with hMC1bR. Analogs of NDP-αMSH with various amino acids in place of Trp9 were synthesized and tested in vitro in receptor affinity binding and cAMP functional assays at human melanocortin receptors 1b, 3, 4, and 5 (hMC1b,3-5R). Several new compounds displayed high agonist potency at hMC1bR (EC50 = 0.5–5 nM) and receptor subtype selectivity greater than 2000-fold versus hMC3-5R. The Trp9 residue of NDP-αMSH was determined to be not essential for molecular recognition at hMC1bR. © 2007 Wiley Periodicals, Inc. Biopolymers 89: 401–408, 2008.

This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com

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