Analogs of α-melanocyte stimulating hormone with high agonist potency and selectivity at human melanocortin receptor 1b: The role of Trp9 in molecular recognition
✍ Scribed by Maria A. Bednarek; Tanya MacNeil; Rui Tang; Tung M. Fong; M. Angeles Cabello; Marta Maroto; Ana Teran
- Publisher
- Wiley (John Wiley & Sons)
- Year
- 2008
- Tongue
- English
- Weight
- 133 KB
- Volume
- 89
- Category
- Article
- ISSN
- 0006-3525
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✦ Synopsis
Abstract
α‐Melanocyte stimulating hormone (αMSH), Ac‐Ser^1^‐Tyr^2^‐Ser^3^‐Met^4^‐Glu^5^‐His^6^‐Phe^7^‐Arg^8^‐Trp^9^‐Gly^10^‐Lys^11^‐Pro^12^‐Val^13^‐NH~2~, 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‐Ser^1^‐Tyr^2^‐Ser^3^‐Nle^4^‐Glu^5^‐His^6^‐D‐Phe^7^‐Arg^8^‐Trp^9^‐Gly^10^‐Lys^11^‐Pro^12^‐Val^13^‐NH~2~, 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 Trp^9^ of NDP‐αMSH in interactions with hMC1bR. Analogs of NDP‐αMSH with various amino acids in place of Trp^9^ 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 (EC~50~ = 0.5–5 n__M__) and receptor subtype selectivity greater than 2000‐fold versus hMC3‐5R. The Trp^9^ residue of NDP‐αMSH was determined to be not essential for molecular recognition at hMC1bR. © 2007 Wiley Periodicals, Inc. Biopolymers 89: 401–408, 2008.
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